BASIC PHARMACOKINETICS - CHAPTER 14: Exams I

CHAPTER 14 Practice Exams: Section 1
Author: Michael Makoid

Reviewer: Vicki Long
ORGANIZATION
Following are several exams which have been used
in previous classes. These exams cover Chapters 1
through 4. Answers (including the graphs) are
included in a format similar to real exam conditions,
and some exams have the problems worked out
completely.
You are encouraged to work out the exams under

conditions similar to how you will take the exam.
You will want to have a calculator, semi-log graph
paper, and scratch paper available. Before you
begin to answer the questions, you will want to: 1)
create the model from the description of the drug’s
pharmacokinetics, 2) graph all of the data as dis-
cussed in the chapters. From these graphs the
answers will become available. Your graphs should
look like the graphs included in the answers. Appli-
cable equations vary by exam and are included at the
beginning of each chapter covered by the exam.
Remember where you are in the course: Learn the
tools; get the pharmacokinetic parameters from
patient information. So in this section you must be
able to analyze pharmacokinetic data and extract the
pharmacokinetic parameters. That means: Assess
the pharmacokinetic description of the drug and cre-
Basic Pharmacokinetics REV. 99.4.25 14-1

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
Practice Exams: Section 1
ate a model, develop equations for the model, graph

the data according to those equations, and get the
parameters out. A student commented, “You mean,
all we have to do is get the slope and intercept from
a couple of graphs and tell you what they mean?”
Yes, that right!
Do not just look at the graphs and the answers and

say, “Yes, that makes sense. I can do this.” You will
be surprised to find out that what looks easy worked
out is not so easy when it isn’t.

Practice Exams: Section 1 : Nifedipine - Section 1
14.1 Nifedipine - Section 1

Masotti et al (J Clin Pcol 1985; 25: 27-35) and Traube et al (ibid 125-9) looked at the hemodynamic pharmacological response of
nifedipine.
14.1.1 NIFEDIPINE DATA

Nifedipine (Procardia ®) is a calcium channel blocker which specifically inhibits potential-dependent channels not
receptor-operated channels, preventing calcium influx of cardiac and vascular smooth muscle (coronary, cerebral).
Calcium channel blockers reduce myocardial contractility and A-V node conduction by reducing the slow inward cal-
cium current. They are indicated in angina, cardiac dysrhythmias, and hypertension among others. Nifedipine
appears to be metabolized entirely into an inactive metabolite, an acid and subsequently further metabolized to a lac-
tone. Both the acid and the lactone are excreted into the urine and the feces.
PROBLEM TABLE 11 - 1. Pharmacological Data
Fall in Diastolic Fall in Diastolic

BP Cp (ng/mL) Time (hr) BP
8 15 1 13.0
10 40 2 12.3
12 100 4 10.7
13 200 5 10.0
9 7.0
Echizen and Eichelbaum (Clin Pkin 1986; 11:425-49) and Kleinbloesem et al (Clin Pcol Therap 1986; 40: 21-8)
reviewed the pharmacokinetics of Nifedipine. While the drug is not routinely given by IV bolus and does not strictly
conform to a one compartment model, let's treat the data as if those problems can be ignored. The following data is
offered for evaluation:
PROBLEM TABLE 11 - 1. Nifedipine IV Bolus Profile
Cp Cm1 Xm1f Xm1u Xm2f Xm2u

Time (hr) (mcg/L) (mcg/L) (mg) (mg) (mg) (mg)
0.5 24.7
1 44.4
2 139 71.8 .14 .59
4 65.6 96.5 .44 1.83 .028 .11
6 31.1 100 .77 3.25 .073 .29
8 14.6 94.7 1.1 4.65 .135 .54
12 76.5 1.69 7.10 .291 1.15
24 34 2.77 11.63 .75 2.95
7 days 3.6 15.1 1.3 5.0

Copyright © 1996 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
14.1.2 NIFEDIPINE QUESTIONS

1) dR/dT = slope of the Pharmacological 18) AUMCiv = Area under the first moment
response vs. time profile (mmHg/hr) of the plasma concentration of Nifedipine vs
time curve of IV dose (mic/L*hr2 )
2) dR/d(lnC) = slope of the Pharmacolog-
ical response vs concentration profile 19) MRTiv = Mean Residence time of
(mmHg) Nifedipine given as the IV dose (hr)
3) d(lnC)/dt = slope of the concentration 20) Xm10 = Mass of acidic metabolite in
vs time profile (hr-1 ) the body at time = 0 (mg)
4) kr = rate constant of excretion of Nife- 21) Xm1inf = Mass of the acidic metabo-
dipine into the urine (hr-1 ) lite in the body at infinite time. (mg)
5) kf = rate constant of excretion of Nife- 22) Vm1 = Volume of distribution of the
dipine into feces (hr-1 ) acidic metabolite in the body (L)
6) km1 = rate of metabolism of Nife- 23) Cm1 = Concentration of acidic metab-
dipine in the body (hr-1 ) olite in the body at time = 0 (mic/L)
7) K1 = elimination rate constant of Nifedipine in Im1 = Intercept of the acidic metabolite con-
the body; the summation of all of the ways that it is centration vs time profile = 181.2 mic/L
removed from the body. (hr-1 )
24) AUCmet = Area Under the Curve of
8) T1/2 of Nifedipine in the body (hr) the metabolite plasma concentration vs
time profile (mic/L*hr)
9) X0 = Mass of Nifedipine in the body
at time 0 (mg) AUMCmet = Area Under the First Moment
Curve of the metabolite plasma concentration vs
10) Xinf = Mass of Nifedipine in the body time profile = 35700 mic/L*hr2
at time infinite time (mg)
25) Xm1u0 = Mass of acidic metabolite
11) Xuinf = Mass of unchanged Nife- in urine at time = 0 (mg)
dipine in the urine at infinite time (mg)
26) Xm1uinf = Mass of acidic metabolite
12) Xfinf = Mass of unchanged Nife- in urine at time = infinity (mg)
dipine in the feces at infinite time (mg)
27) Xm1f0 = Mass of acidic metabolite in
13) V = Volume of distribution of Nife- feces at time = 0 (mg)
dipine (L)
28) Xm1finf = Mass of acidic metabolite
14) Cp0 = Concentration of Nifedipine in in feces at time = infinity (mg)
the body at time 0. (mic/L)
29) Km1u = Rate constant of excretion of
15) AUCiv = Area under the plasma con- acidic metabolite into urine (hr-1 )
centration of Nifedipine vs time curve of
the IV dose (mic/L*hr) 30) Km1f = Rate constant of excretion of
acidic metabolite into feces (hr-1 )
16) First trapazoid of the AUCiv (mic/
L*hr) 31) Km2=Rate constant of formation of
lactone metabolite in body =rate of metabolism of
17) Last trapazoid of the AUCiv (mic/ the acidic metabolite in the body (hr-1 )
L*hr) 32) K2 = Km1f + Km1u + Km2 = sumation of
all of the ways that the acidic metabolite is eliminated from the
body (hr-1 )

33) Xm20 = Mass of lactone metabolite 38) Xm2finf = Mass of lactone metabolite
in body at time = 0 (mg) in feces at time = infinity (mg)
34) Xm2inf = Mass of lactone metabolite K3 = Km2f + Km2u = the sumation of all of
in body at time = infinity (mg) the ways that the lactone can be eliminated =
0.138 hr.-1
35) Cm2inf = Concentration of lactone
metabolite in the body at time = infinity (0) 39) Km2u = Rate constant of excretion of
lactone metabolite into urine (hr -1 )
36) Xm2u0 = Mass of lactone metabolite
in urine at time = 0 (mg) 40) Km2f = Rate constant of excretion of
lactone metabolite into feces (hr -1 ) .
37) Xm2uinf = Mass of lactone metabo-
lite in urine at time = infinity (mg)
PROBLEM TABLE 11 - 1. Answer Pool Any number from the answer pool may be used
once, more than once, or not at all
Negative Numbers Small Numbers Big Numbers

A -0.0001 0 13
B -0.0010 0.010 15.1
C -0.0100 0.018 17
D -0.0180 0.028 20
E -0.0280 0.042 25
F -0.0375 0.070 38.9
G -0.0750 0.085 50
H -0.0850 0.110 85
I -0.110 0.138 170
J -0.138 0.375 181.2
A -0.375 0.750 295
B -0.750 1.30 415
C -1.30 1.85 434
D -1.85 2.0 787
E -2.0 2.67 2100
F -2.67 3.6 3570
G -3.6 5.0 8500
H -5.0 7.5 21000
I -7.5 8.5 35700
J -10 9.9 85000

14.1.3 NIFEDIPINE SOLUTIONS

X
km1
Xmf1 kmf1 Xm1 kmu1 Xmu1
km2
Xmf2 kmf2 Xm2 kmu2 Xmu2
Graph #1 Graph #2
- 0.75 mmHg/hr
Nifedipine R vs T
14 14
13
13
12
RESPONSE (MMHG)
12
11
11
10
Response (mmHg)
9
10
8
9 7
2 mm Hg
6
8
0 2 4 6 8 10
101 102 103
Time (hr)
Concentration (ng/mL)
/mL)
L)
Graph #3 Nifedipine IV Bolus Graph #4

Nifedipine IV bolus - Metabolite
103
103
181.2 mic/L = Intercept (given)
CONCENTRATION MIC/L
CONCENTRATION MIC/L
100
102
102
50 1.85 hr
10 hrs
101
2 3 4 5 6 7 8 101
0 4 8 12 16 20 24
Time (hours)
Time (hours)

dR
1. ------- = – 0.75mmHg ⁄ hr Slope from graph # 2
dT
dR
2. ------------ = 2.0mmHg Slope from graph # 1
d ln C
dR
-------
3. d------------ dT - = –-------------
ln C = ------------ 0.75 = – 0.375hr –1 Answer #1-
-------------------------
dT dR
------------ 2 Answer #2
d ln C
4. kr = 0, Nifedipine is not excreted into the urine, it is metabolized entirely K1 = k m1 from pkin description
5. kf = 0, Nifedipine is not found in the feces, only the metabolites are. K1 = k m1 from pkin description
0.693 –1
6. km1, Rate of metabolism of Nifedipine in the body = ---------------- = 0.375 hr from graph #3
1.85hr
–1
7. K1, Elimination rate constant of Nifedipine in the body = 0.375hr from graph #3
8. T 1 ⁄ 2 = 1.85 hr from graph #3
9. Xo = ( 3.6 + 15.1 + 1.3 + 5.1 ) = 25mg from pkin description = Σ ( X mu1 + X mu2 + X mf 1 + X mf2 )
10. Xinf = 0 from pkin description
11. X u ( inf ) = 0 from pkin description
12. X f ( inf ) = 0 from pkin description
Dose- = -------------------------
25mg - • 1000mic
13. V = ------------ --------------------- = 85L
Cp o 295mic ⁄ L 1mg
14. 295mic ⁄ L Cp0 extrapolated back to t = 0 obtained from graph #3

Cp 295 = 787mic ⁄ L ⋅ hr
15. AUC iv = ---------o = ------------- as an estimate. Using Trapazoidal rule:
k 0.375
 Cp o + Cp 1 Cp 1 + Cp 2 Cp 2 + Cp 3 Cp 3 + Cp last Cp last 
Σ  -------------------------
- ⋅ ∆t 1 + -------------------------
- ⋅ ∆t2 + -------------------------
- ⋅ ∆t 3 + ------------------------------- ⋅ ∆t last + --------------- 
 2 2 2 2 K1 
 14.6 mcg
Σ  295 + 139- ⋅ 2 + 139
----------------------- + 65.6 ⋅ 2 + 65.6
------------------------- + 31.1- ⋅ 2 + 31.1
-------------------------- + 14.6- ⋅ 2 + -------------
-------------------------- ----------hr
 2 2 2 2 0.375  L
Σ { 434 + 204.6 + 96.7 + 45.7 + 38.9 } mcg

----------hr = 821.9mcg
----------hr
L L

16
Cp o + Cp 1
-------------------------- ⋅ ∆t =  (----------------------------
295 + 139 )- ⋅ 2 = 434mic ⁄ L ⋅ hr
2  2 
Cp L 14.6
17. ---------- = ------------- = 38.9mic ⁄ L ⋅ hr
k 0.375
2
18 AUMC = AUC ⋅ MRT = 787 ⋅ 2.67 = 2100mic ⁄ L ⋅ hr estimate. Using the trapazoidal rule:
 T 0 ⋅ C p o + T1 ⋅ C p1 T1 ⋅ C p1 + T 2 ⋅ C p 2 T2 ⋅ C p2 + T3 ⋅ C p3 T 3 ⋅ C p 3 + T last ⋅ C p last T last ⋅ C p last Cp last 

Σ  ----------------------------------------------
- ⋅ ∆t 1 + ----------------------------------------------
- ⋅ ∆t 2 + ----------------------------------------------
- ⋅ ∆t 3 + ---------------------------------------------------------
- ⋅ ∆t last + ------------------------------
- + ---------------
2
 2 2 2 2 K1 K1 
 0 ⋅ 295 + 2 ⋅ 139 2 ⋅ 139 + 4 ⋅ 65.6 4 ⋅ 65.6 + 6 ⋅ 31.1 6 ⋅ 31.1 + 8 ⋅ 14.6 8 ⋅ 14.6 14.6  mcg 2
Σ  --------------------------------------- ⋅ 2 + ---------------------------------------- ⋅ 2 + ------------------------------------------ ⋅ 2 + ------------------------------------------ ⋅ 2 + ------------------ + ----------------  ----------hr
 2 2 2 2 0.375 0.375  L
2
mcg 2
Σ { 278 + 540.4 + 449 + 303.4 + 311.47 + 103.82 } = 1986.1----------hr
L
1
19. MRT iv = --- = 2.67hr estimate. Using trapazoidal rule and definitions
k
mcg 2 mcg 2
AUMC trap 1986.1----------hr AUMC est 2100 ----------hr
L L
MRT IV = --------------------------- = ------------------------------------ = 2.42 hr ≅ ------------------------ = ------------------------------- = 2.67 hr
AUC trap mcg AUC est mcg
821.9----------hr 787 ----------hr
L L
20. X m1 ( o ) = 0 from pkin description
21. X m1 ( inf ) = 0 from pkin description
22. Vm1 = 170L

k m1 ⋅ X 0 –K2t – K1t
From LaPlace transforms, the equation for the metabolite is - {e
Cp m = --------------------------------------- –e }
( K1 – K2 ) ⋅ V dm
m1 0 k ⋅X
the intercept, I, given as 181.2 mic/L in the data = ---------------------------------------
- .
( K1 – K2 ) ⋅ V dm
k m1 ⋅ X 0 0.375 ⋅ 25mg
Thus V dm = ----------------------------------------------------- = ---------------------------------------------------------------- = 169.6 L
mic mg
( K1 – K2 ) ⋅ 181.2--------- ( 0.375 – 0.07 ) ⋅ 0.1812-------
L L
23. C m1 ( 0 ) = 0 from pkin description

24. AUC met = 2100mic ⁄ L ⋅ hr
PROBLEM TABLE 11 - 1. Nifedipine Data
Cpm ( n ) + Cpm ( n + 1 ) t
-------------------------------------------------------- t AUC
Time (hr) Cpm (mcg/L) 2 ∆T ( n ) AUC trap 0
0 0
0.5 24.7 0 + 24.7 0.5 6.175 6.175
-------------------
2
1 44.4 24.7 + 44.4 0.5 17.275 23.45
---------------------------
2
2 71.8 44.4 + 71.8 1 58.1 81.55
---------------------------
2
4 96.5 71.8 + 96.5 2 168.3 249.85
---------------------------
2
6 100 96.5 + 100 2 196.5 446.35
-------------------------
2
8 94.7 100 + 94.7 2 194.7 641.05
-------------------------
2
12 76.5 94.7 + 76.5 4 342.4 983.45
---------------------------
2
24 34 76.5 + 34 12 663 1646.45
----------------------
2
∞ 0 Cpm last 485.7 2132.15
+ -------------------
-
K small
25. X m1u ( 0 ) = 0 from pkin description
26. X m1u ( inf ) = 15.1mg given in data
27. X m1f ( 0 ) = 0 from pkin description
28. X m1f ( inf ) = 3.6mg given in data
k m1u Xm1u k m1u

= 15.1mg
–1 –1
29. k m1u = 0.042hr ----------- = ------------ = -------------------- ------------------ thus k m1u = 0.042hr
K2 Xo – 1 25mg
0.07hr
k m1f X m1f k m1f
= 3.6mg
–1 –1
30. k m1f = 0.01hr ---------- = ----------- = -------------------- --------------- thus k m1f = 0.01hr
K2 Xo –1 25mg
0.07hr
–1 –1 –1 –1
31. k m2 = 0.018hr 0.07 hr = K 2= k m1f + k m1u + k m2 = 0.01 hr + 0.042 hr + k m2

–1
32. K2 = 0.07hr From your LaPlace Transforms, you know that the equation is bi-exponential, with one of
the slopes being K1 and the other being K2. The terminal slope of graph #4 is 0.07 hr -1, which is not K1 (0.375 hr -1).
So it must be K2.
33. X m2 ( 0 ) = 0 from pkin description
34. X m2 ( inf ) = 0 from pkin description
35. C m2 ( inf ) = 0 from pkin description
36. X m2u ( 0 ) = 0 from pkin description
37. X m2u ( inf ) = 5.0mg given in data
38. X m2f ( inf ) = 1.3mg given in data
–1 k m2u k m2u X m2u 5.0mg

39. k m2u = 0.11hr ----------------------- = ----------
- = ----------------------------- = ------------------------------------
-
–1 K3 X m2u + Xm2f 5.0mg + 1.3mg
0.138hr
–1 k m2f k m2f Xm2f 1.3mg -

40. k m2f = 0.028hr ----------------------- = ---------
- = ----------------------------- = ------------------------------------
–1 K3 X + X 5.0mg + 1.3mg
0.138hr m2u m2f

Practice Exams: Section 1 : Enalapril - Section 1
14.2 Enalapril - Section 1

Citation
14.2.1 ENALAPRIL DATA

Enalapril (Vasotec ®) is an angiotensin converting enzyme (ACE) Inhibitor effective in the treatment of hypertension
and chronic heart failure (CHF). The parent compound is weakly active, while its sole metabolite, Enalaprilat, exhib-
its almost all of the pharmacological activity. Original work on the pharmacokinetics of Enalapril showed the parent
drug, Enalapril and its metabolite, Enalaprilat, show up in both feces and urine.
The following data was offered regarding the Pharmacological response of Enalaprilat as judged by the fall in Seated
Systolic Blood Pressure (SSBP).
PROBLEM TABLE 11 - 1. Enalapril - Section 1: Pharmacological Profile
Fall in SSBP Time (hr) after Fall in SSBP

(mmHg) Max Dose (mg) (mmHg)
15 3 1 0
12 7 5 1
10 10 10 5
8.6 12 15 10
6 18 20 16
4 24 25 20
30 24
PROBLEM TABLE 11 - 1. Enalapril - Section 1 IV Bolus Profile from a 5 mg dose
Cumulative Cumulative Cumulative

Cumulative Enalapril Enalaprilat Enalaprilat
Time Cp Cpm Enalapril in in feces in urine in feces
(hr) (ng/mL) (ng/ml) urine (mg) (mg) (mg) (mg)
1 29 7.5 0.41 0.12
2 17 11.6 0.65 0.20
3 10 13.8 0.80 0.24
4 5.9 14.9 0.88 0.26
6 2 15.2 0.96 0.30
8 14.7
10 13.8
20 9.8
30 6.9
40 4.9
50 3.4 1.0 0.3 2.25 1.45

The intercept of Cp m vs t was found to be 19.8 ng ⁄ mL and a total of 2.25 mg of enalaprilat was found in the
urine while 1.45 mg was found in the feces.
PROBLEM TABLE 11 - 1. Enalapril Answer Pool
Negative Small Small Medium Large

Numbers Numbers Numbers Numbers Numbers
A 0.000 0.014 1.00 14.5 100
B -0.014 0.021 1.45 19.8 174
C -0.021 0.030 .1.90 30.3 528
D -0.030 0.035 2.25 33.0 395
E -0.035 0.039 3.75 37.5 693
F -0.110 0.110 5.00 39.5 834
G -0.390 0.150 6.93 50.0 1740
H -0.530 0.300 8.00 70.0 5280
I -0.700 0.390 9.00 94.0 14400
J -0.900 0.530 9.76 97.0 16000
Equation Answer Pool:
k mu k m Xo 1 – e – K2t 1 – e – K1t ( k mf k m Xo ) 1 – e –K2t 1 – e – K1t

A ------------------------
- --------------------- – --------------------- B ------------------------
- --------------------- – ---------------------
( K1 – K2 ) K2 K2 ( K1 – K2 ) K2 K1
km ⋅ X 0 k mu k m Xo
C ---------------------------------------- ⋅ – K2t K1t D. ------------------------- ⋅ – K2t K1t
( K1 – K2 ) ⋅ Vd m ( e ) – (e ) ( K1 – K2 ) ( e ) – (e )
km ⋅ X 0 X 0 – K1t
E ------------------------- ⋅ – K2t K1t F ------ e
( K1 – K2 ) ( e ) – (e ) V
– K1t k – K1t
G kr ⋅ X 0 e H ------f- ⋅ X0 ( 1 – e )
K1
k – K1t – K1t
I ------u- ⋅ X0 ( 1 – e ) J X0e
K1

14.2.2 ENALAPRIL QUESTIONS

Find the equation for: 18) kmf, the fecal excretion rate constant
for metabolite, Enalaprilat, in plasma.
1) X, the mass of parent drug, Enalapril, in
the body. 19) K1, the elimination rate constant of
parent drug in plasma(the summation of all
2) Xu, the mass of parent drug, Enalapril,
processes which remove Enalapril)
in urine.
20) K2, the elimination rate constant of
3) dX u/dt, the rate of excretion of parent metabolite in plasma(the summation of all
drug, Enalapril, in urine. processes which remove Enalaprilat).
4) Xf, the mass of parent drug, Enalapril, in
feces.
Find the intercept of the graph of:
5) Xm, the mass of metabolite, Enalaprilat,
21) Cp vs T
in the body.
22) Cpm vs T (terminal extrapolated line)
6) Xmu, the mass of metabolite, Enalapri-
lat, in urine. 23) dXu/dt vs T
7) dXmu/dt, the rate of excretion of metab- 24) dXf/dt vs T
olite, Enalaprilat, in urine.
8) Xmf, the mass of metabolite, Enalapri-
Find the slope of the terminal portion of
lat, in feces.
the graph of:
9) Cp, the plasma concentration of parent
25) Cp vs T
drug, Enalapril.
26) Cpm vs T
10) Cpm, the plasma concentration of
metabolite, Enalaprilat. 27) dXu/dt vs T
28) dXf/dt vs T
Find the value of:
11) dR/dT Find the area under the curve of the
12) dR/d(ln(C)) graph of
13) d(ln(C))/dT 29) Cp vs T(first trapazoid only)
14) kr, the renal excretion rate constant of 30) Cpm vs T(first trapazoid only)
parent drug, Enalapril, in plasma.
31) Cp vs T(from Tlast to T ∞ only)
15) kf, the fecal excretion rate constant of
parent drug, Enalapril, in plasma. 32) Cpm vs T(from Tlast to T ∞ only)
16) km, the metabolism rate constant
ofparent drug, Enalapril, in plasma. 33) Cp vs T
17) kmu, the renal excretion rate constant 34) Cpm vs T

for metabolite, Enalaprilat, in plasma. 35) dXu/dt vs T

36) dXmu/dt vs T 49) XMU0

37) T*Cp vs T 50) XMF0
38) T*Cpm vs T 51) X ∞
Find the value of :
52) X u ∞
39) AUC(enalapril)
40) AUMC(enalapril) 53) X f ∞
41) MRT(enalapril) 54) X m∞

42) AUC(enalaprilat) ∞
55) X mu
43) AUMC(enalaprilat)
∞
56) X mf
44) MRT(enalaprilat)
57) Cp0
45) X0
58) Cpm0
46) XU0
59) Vd
47) XF0
60) Vdm
48) XM0
14.2.3 ENALAPRIL SOLUTIONS

Enalapril Model
kf kr
Xf X Xu
km
kmf kmu
Xmf Xm Xmu

sponse
esponse
R vs C RESPONSE DATA
R vs T
24
15
22
14
20
13
18
12
16
14
11
12 10
10 9
8
10 10
2 4 6 8 10 12
Concentration
Time (hr)
Enalapril Enalapril IV Bolus - Metabolite
102
102
101
101
100
0 1 2 3 4 5 6
100
Time (hrs) 0 10 20 30 40 50
Time (hours)

– k1t
1 X = Xoe
k – k1t
2 X u = ----r- X o ( 1 – e )
k1
– k1t
3 dx u ⁄ dt = k r Xo e
k – k1t
4 X f = -----f Xo ( 1 – e )
k1
km X o – k2t – k1t
5 -(e
Xm = -------------------- –e )
( k1 – k2 )
k mu k m Xo 1 – e –k2t 1 – e –k1t
6 Xmu = --------------------- -------------------- – --------------------
( k1 – k2 ) k2 k1
dX mu k mu k m Xo – k2t – k1t
7 ------------- = --------------------- ( e –e )
dt k1 – k2
( k mf k m Xo ) 1 – e – K2t 1 – e –K1t
8 X mf = ------------------------
- --------------------- – ---------------------
K1 – K2 K2 K1
– k1t D- e – k1t
9 C p = C po e = ------
Vd
km ⋅ X 0
10 -⋅
Cp m = --------------------------------------- – K2t K1t
( K1 – K2 ) ⋅ Vd m ( e ) – (e )
11 dR ⁄ dt = – 0.7
12 dR ⁄ d ( ln c ) = 20
13  d ( ln c ) ⁄ dt = –----------
0.7 = – 0.035
 20 
∞
Xu
- • k 1 = 1--- • 53 = 0.106 = 0.11hr
–1
14 k r = ------
Xo 5
∞
Xf
- • k 1 = 0.3
–1
15 k f = ------ ------- • 0.53 = 0.0318 = 0.03 hr
Xo 5

∞ ∞
Xmu + X mf
• k 1 = 2.25 + 1.45- • 0.53 = 0.39 hr – 1
16 k m = ------------------------ --------------------------
Xo 5
∞
Xmu
• k 2 = 2.25
–1
17 k mu = ------------------------ ---------- • 0.035 = 0.21hr
∞ ∞ 3.7
Xmu + Xmf
∞
Xmf
• k 2 = 1.45
–1 –1
18 k mf = ------------------------ ---------- ⋅ 0.035hr = 0.014 hr
∞ 3.7
Xmu + Xmf
–1
19 K1 = 0.53hr = slope of Cp vs T = k m + kf
–1
20 K2 = 0.035hr = terminal slope of graph Cp m vs T = k mu + k mf
21 Cp ( 0 ) = 50ng ⁄ mL
22 I = 19.8 ng ⁄ mL
dX
23 --------u- vs T I = 0.53
dt
24 k f ⋅ X0 = ( 0.03 ⋅ 5 ) = 0.15ng ⁄ mL
PROBLEM TABLE 11 - 1. Urinary Rate Set up
∆Xu ∆X u
∆X u ---------- ----------
T mid Time ∆T Xu ∆T ∆T
0 0
0.5 1 1 0.41 0.41 0.41 ⁄ 1 0.41
1.5 2 1 0.65 0.24 0.24 ⁄ 1 0.24
2.5 3 1 0.80 0.15 0.15 ⁄ 1 0.15
3.5 4 1 0.88 0.08 0.08 ⁄ 1 0.08
5 6 2 0.96 0.08 0.08 ⁄ 2 0.04
–1
25 0.53 hr
–1
26 0.035 hr

–1 16000
27 0.53 hr 44 --------------- = 30.3hr
528
–1
28 0.53 hr
45 X 0 = 5mg
29
( 50 + 29 )- ⋅ 1 = 39.5ng ⁄ mL ⋅ hr 46 Xu ( 0) = 0
----------------------
2
47 Xf ( 0 ) = 0
30
( 0 + 7.5 ) ⋅ 1 = 3.75ng ⁄ mL ⋅ hr 48 Xm ( 0 ) = 0
---------------------
2
49 Xmu ( 0 ) = 0
2
31 ---------- = 3.77ng ⁄ mL ⋅ hr 50 Xmf ( 0 ) = 0
0.53
3.4 - = 97ng ⁄ mL ⋅ hr ∞
32 ------------ 51 X = 0
0.035
∞
52 Xu = 1mg
33 94 ng ⁄ mL ⋅ hr
34 53
∞
Xf = 0.3mg = ( 5 – 1 – 2.25 – 1.45 )
19.8  ------------ 1 - = 528ng ⁄ mL ⋅ hr
1 - – ---------
0.035 0.53
∞
54 Xm = 0
dX
35 AUC  --------u- vsT = 1mg ∞
 dt  55 X mu = 2.25mg
dX mu ∞
36 AUC  ------------
- vsT = 2.25mg 56 X mf = 1.45mg
 dt 
57 Cp 0 = 50ng ⁄ mL
2
37 174 ng ⁄ mL ⋅ hr
58 Cp m ( 0 ) = 19.8ng ⁄ mL
2
38 16000 ng ⁄ mL ⋅ hr
dose- = 100L
39 94 ng ⁄ mL ⋅ hr Vd = ------------
Cp ( 0 )
59
2
40 174 ng ⁄ mL ⋅ hr 60
41 1.9 hr ( km ⋅ X0 ) ( 0.39 ⋅ 5 )
Vd m = --------------------------- = -----------------------------------------------------
( K1 – K2 )I ( K1 – K2 ) ( 0.0198
42 528 ng ⁄ mL ⋅ hr
2
43 16000 ng ⁄ mL ⋅ hr

Practice Exams: Section 1 : Ciprofloxacin Section 1
14.3 Ciprofloxacin Section 1
14.3.1 CIPROFLOXACIN DATA

Ciprofloxacin (Cipro ®) is a fluoroquinolone, synthetic broad spectrum antibacterial agent. It is reasonably well
absorbed orally and is excreted into the urine and is metabolized to four known metabolites which are also excreted
into the urine. Before an accurate analytical assay was worked out for ciprofloxacin, a microbiological assay was used
to determine the pharmacokinetics. This assay utilized the ability of ciprofloxacin to kill microorganisms grown on an
agar plate and create a clear zone of no growth, the zone of inhibition. The following data was collected from that pro-
cedure: (Intercept for the extrapolated metabolite graph was 0.372 mg/L)
PROBLEM TABLE 11 - 1.
Data Set 0ne Data Set Two
Pharmacological Response Pharmacological Response

Zone -mm Time (hrs) zone - mm Concentration Spiked plasma
27 1 4.7 0.01
23.2 5 13.5 0.05
20.4 8 17.3 0.1
18.5 10 19.5 0.15
5.2 24 21 0.2
23.5 0.3
28 0.7
PROBLEM TABLE 11 - 1. Data from 500 mg IV Bolus Cipro.
Time Cp Cpm Interval Cipro (mg)

(Hrs) (mg/L) (mg/L) (hours) in urine
0.5 0.045 0-4 184
1 3 0.077 4-8 92
2 2.53 0.115 8 - 12 46
3 2.12 0.129
4 1.79 0.128
5 0.119
6 1.26 0.108
8 0.893 0.084
10 0.062
12 0.045
16 0.023
18 0.016
20 0.012

14.3.2 CIPROFLOXACIN QUESTIONS

From the above information find the pharmacokinetic parameters:
1) K (elimination rate constant of Cipro) (hr-1 )
2) kr (urinary excretion rate constant of Cipro)(hr-1 )
3) km (metabolism rate constant of Cipro)(hr-1 )
4) kmu (urinary excretion rate constant of the metabolites)(hr-1 )
5) Cp0 (IV bolus Cipro) (mic/mL)
6) Vd (Cipro)(L.)
7) Vdm (metabolites)(L.)
8) AUC (Cp vs t for Cipro by IV bolus) (mic/mL * hr)
9) AUMC (t*Cp vs t for Cipro by IV bolus (mic/mL * hr2)
10) MRT (Cipro)(hr)
11) AUC (dXu/dt vs t(mid) for Cipro by IV bolus) (mg)
12) Xinf (Cipro in the body at infinite time)
13) Xuinf (Cipro in the urine at infinite time)
14) Xminf (metabolites in the body at infinite time)
15) Xmu inf (metabolites in the urine at infinite time)
16) T1/2 (Cipro)(hr)
17) Clearance (Cipro)(L/hr)

18) dR/dT (mm/hr)
19) dR/d(lnC) (mm)
20) d(lnC)/dt (Cipro)(hr-1)
21 Slope of Cp vs T ([Cipro] vs t) on semi-log paper
22 Slope of dXu/dt vs T(mid) vs t on semi-Log paper
23 Slope of terminal portion of Cpm vs T on semi-log paper
24) Slope of stripped portion of Cpm vs T on semi-log paper
25) Equation for the rate of formation of the metabolites in the urine (dXmu /dT vs T)
a) kmu * Xo * (e-Kt - e-kmut ) / (kmu - K)
b) kmu * km * Xo * (e-Kt - e-kmut ) / (K - kmu)
c) km * Xo * (e-Kt - e-kmut ) / (kmu - K)
d) kmu * km * Xo * {(1-e-Kt )/K- (1-e-kmut )/kmu} / (kmu - K)
e) kmu * km * Xo * (e-Kt - e-kmut ) / (kmu - K)

14.3.3 CIPROFLOXACIN SOLUTIONS

Ciprofloxacin Model
X ku Xu
km
Xm kmu Xmu
Ciprofloxacin
30 Ciprofloxacin
30
25
25
20 20
Response (zone - mm)
15 15
Response (zone - mm)

10
10 5
5 0
0 10 -2 10 -1 10 0
0 5 10 15 20 25
Concentration (mic/mL)
Time (hr)
Ciprofloxacin Ciprofloxacin Metabolite data Ciprofloxacin Urine data

101 100 102
100 10-1
10 -1 10-2
dXu/dt (mg)
101
0 5 10 15 20
0 2 4 6 8
0 2 4 6 8 10
Concentration (mic.mL)
Time (hours) Time (hours)

Tmid (hours)

–1 ∞
1. K = 0.173hr 15 X mu = 125mg
2.
16 T 1 ⁄ 2 = 4.0hr
R ⁄ hr- = 0.13hr – 1
k r = -----0- = 65.13mg
------------------------------
X0 500mg 17 Cl = 24.2L ⁄ hr
dR
3 k m = 0.043hr
–1 18 ------- = – 0.95mm ⁄ hr
dT
–1
4 k mu = 0.462hr dR = 5.5mm
19 -----------------
d ( ln C )
5 Cp 0 = 3.57mic ⁄ mL
20
( ln C ) = – 0.173hr –1
d-----------------
6 Vd = 140L dt
7 Vd m = 200L 21 Slope of Cp vs T = – 0.173
22 Slope of
8 AUC = 20.7mic ⁄ mL ⋅ hr
dX u
Cp vs T --------- vs ( t mid ) = – 0.173
dt
9.
2 23 Slope of terminal portion of
AUMC = 119.7mic ⁄ mL ⋅ hr
Cp m vsT = – 0.173
10 MRT = 5.8hr
24 Slope of stripped portion of
dX u Cp m vsT = – 0.462
11 AUC = 375mg ---------vs ( t mid )
dt
25
12
∞
X = 0 k mu ⋅ k m ⋅ X 0 – Kt – kmut
----------------------------- • (e – e )
( k mu – K )
∞
13 X u = 375mg
∞
14 Xm = 0

Practice Exams: Section 1 : Methylphenidate Section 1
14.4 Methylphenidate Section 1

Citation
14.4.1 METHYLPHENIDATE DATA

Methylphenidate (MP) (Ritalin®) is an effective stimulant in the treatment of narcolepsy in adults and attention deficit
syndrome in children. It is entirely metabolized to the inactive metabolite, Ritalinic Acid (RA), by the liver which is
subsequently excreted unchanged into the urine. Pharmacological response was measured objectively using sleep
latency as measured by encephalography. Sleep latency is the time required to fall asleep in a darkened quiet room.
Pharmacological Response Data
Time (hr) Response (min) Cp (mcg/mL) Response (min)

0.5 22 6 22.5
1 16 5 18
1.5 10 4 15
2 5 3 10
PROBLEM TABLE 11 - 1. Plasma Profiles

(Intercept of extrapolated RA line 0.21
mic/mL)
Plasma Vs. Time Profile

10 mg MP given by IV Bolus
Cp (MP) Cpm (RA)

Time (hr) (mcg/mL) (mcg/mL
0.5 0.091 0.022
1 0.067 0.029
1.5 0.049 0.030
2 0.035 0.028
2.5 0.026 0.024
3 0.019 0.020
4 0.010 0.012
6 0.003 0.004
8 ------- 0.0013

14.4.2 METHYLPHENIDATE QUESTIONS:

From the above information find the phar- 25) d(lnCp)/dt (MP)(hr-1)
macokinetic parameters:
26) The slope of Cp vs T ([MP] vs t) on
1) K (elimination rate constant of MP) (hr -1
semi-log paper
)
27) The equation for Cp vs T ([MP] vs t)
2) kr (urinary excretion rate constant of on semi- log paper
MP)(hr-1 )
28) The slope of terminal portion of
3) km (metabolism rate constant of dXmu/dt vs T(mid) on semi-Log paper
MP)(hr-1 )
29) The equation for dXmu/dt vs T(mid)
4) kmu (urinary excretion rate constant of on semi- log paper
(RA)(hr-1 )
30) The slope of terminal portion of Cpm vs
5) Cp0 (IV bolus MP) (mic/mL) T ([RA] vs t) on semi-log paper
6) Vd (MP)(L.) 31) The equation for Cpm vs T ([RA] vs t)

on semi- log paper
7) Vdm (RA)(L.)
32) The slope of stripped portion of Cpm vs
8) AUC (Cp vs t for MP by IV bolus) (mic/
T ([RA] vs t) on semi-log paper
mL * hr)
33) The equation for Xm (bar) (Laplace domain
9) AUMC (t*Cp vs t for MP by IV bolus equation for RA in the body)
(mic/mL * hr2)
34) The equation for Xm (RA in the body)
10) MRT (MP)(hr)
11) AUC (dXu/dt vs t(mid) for MP by IV
bolus) (mg)
12) AUC (dXmu vs t(mid) for RA)(mg)
13) X0 (MP in the body at zero time)
14) Xm0 (RA in the body at zero time)
15) Xmu0 (RA in the urine at zero time)
16) X1hr (MP in the body at 1 hr.)
17) Xm1hr (RA in the body at 1 hr)
18) Xinf (MP in the body at infinite time)
19) Xuinf (MP in the urine at infinite time)
20) Xminf (RA in the body at infinite time)
21) T1/2 (MP)(hr)
22) Clearance (MP)(L/hr)

23) dR/dT (min/hr)
24) dR/d(lnCp) (%)

14.4.3 METHYLPHENIDATE SOLUTIONS
km
Xm kmu Xmu
Methyl Phenidate R vs C
24
25
Response
22
20 20
0 1
18
15
16
10
Response (min)
14
12
5
10
0 8
10 10
0.5 1.0 1.5 2.0
Concentration
Time (hr)
Methyl Phenidate IV Bolus MP IV Bolus - Metab

100 100
10-1 10-1
10-2
10-2
0 1 2 3 4
0 2 4 6 8
Time (hours)
Time (hours)

–1 21 T 1 ⁄ 2 = 1.1hr
1 K = 0.63hr
2 kr = 0 22 Cl = 50.4L ⁄ hr
dR
3 k m = 0.63hr
–1 23 ------- = – 11.4min ⁄ hr
dT
–1
4 k mu = 0.90hr dR - = 17.5 min
24 --------------------
d ( ln Cp )
5 Cp 0 = 0.125mic ⁄ mL
25
( ln Cp )- = – 0.63hr –1
d--------------------
6 Vd = 80L (change in answer dT
pool)
–1
26 The slope of Cp vs T – 0.63hr
7 Vd m = 115L (change in answer
27 The equation for Cp vsT
pool)
–k ⋅ t
Cp = Cp 0 ⋅ e
8 AUC = 0.20mic ⁄ mL ⋅ hr
9. 28 The slope of terminal portion of
2 dX mu
AUMC = 0.315mic ⁄ mL ⋅ hr ------------
- vsT mid = – 0.63
dT
10 MRT = 1.57hr
29 The equation for
11 AUC = 0 MP is not excreted in dX mu k mu ⋅ k m ⋅ X0 – K1t
the urine ------------- vsT mid = ----------------------------- (e –e )
dT ( K2 – K1 )
12 AUC = 10mg All of RA is 30 the slope of the terminal portion of
excreted in the urine Cp m vsT ( RA )vsT = –0.94
13 X0 = 10mg
31 The equation for
14 Xm ( o ) = 0 km ⋅ X0 – K1t
Cp m vsT ( RA ) = ------------------------- (e –e )
( K2 – K1 )
15 Xmu ( 0 ) = 0
32 The slope of stripped portion
16 X1hr = 5.3 (change in answer – 0.79
pool) km ⋅ X0
33 Xm = ---------------------------------------------
-
17 Xm1hr = 2.8 (change in answer ( s + K1 ) ⋅ ( s + K2 )
pool) 34 The equation for
∞ km ⋅ X 0 – K1t – K 2t
18 X = 0 Xm = ------------------------- (e –e )
( K2 – K1 )
∞
19 Xu = 0
∞
20 Xm = 0

Practice Exams: Section 1 : Adinazolam - Section 1
14.5 Adinazolam - Section 1

Fleishaker [Pharm Res 8 (2): 162-7(1991),Pharm Res 6 (5): 379-86(1989),Psychopharm 99:34-9(1989),Psychopharm 105:181-
5(1991)];Kroboth [J Clin Pharmacol 31:580-6(1991)]; Wagner [Biopharm Drug Dis 8:405-25(1987)].
14.5.1 ADINAZOLAM DATA

Adinazolam (AD) is a triazolobenzodiazepine prodrug which has been shown to have antidepressant activity through
its metabolite, N-desmethyladinazolam (NDMAD). Both AD and NDMAD are excreted into the urine. The following
data regarding AD and NDMAD was collected from the works cited. AD appears to interfere with mental ability. One
of the tests was the ability to Substitute Digits for Symbols (DSST) and the interference of that process was the
response measured below:
PROBLEM TABLE 11 - 1. Pharmacological Response
% Pharm Response Time (hrs) % Pharm Response NDMADC Conc (ng/,L)

59.7 2 33 200
45.3 4 48 300
29.5 6 59 400
15.5 8 68 500
0 12 74 600
From the above information find the pharmacokinetic parameters:
PROBLEM TABLE 11 - 1. Five mg IV bolus dose of AD yieled: (intercept of extrapolated metabolite line is 150 ng/mL)
Plasma Data Urine Data
Time (mid)
Time Cp (AD) Cpm(NDMAD) AD Ecretion Rate
(hr) (ng/mL) (ng/mL) t (mg/hr)
0.5 47 0.5 0.56
1 40 15.4 1 0.48
2 28 23.5 2 0.34
3 27.3 4 0.18
4 14.7 28 6 0.09
5 27
6 7.5 24.9
8 20
10 15
12 11
15 7.5
18 4.2
20 2.8
22 1.9
24 1.2

14.5.2 ADINAZOLAM QUESTIONS

1) K (elimination rate constant of AD) (hr-1 )
2) kr (urinary excretion rate constant of AD)(hr-1 )
3) km (metabolism rate constant of AD)(hr-1 )
4) kmu (urinary excretion rate constant of NDMAD)(hr -1 )
5) Cp0 (IV bolus AD) (ng/mL)
6) Vd (AD)(L.)
7) Vdm (NDMAD)(L.)
8) AUC (Cp vs t for AD by IV bolus) (ng/mL * hr)
9) AUMC (t*Cp vs t for AD by IV bolus (ng/mL * hr2)
10) MRT (AD)(hr)
11) AUC (dXu/dt vs t(mid) for AD by IV bolus) (mg)
12) Xinf (AD in the body at infinite time)
13) Xuinf (AD in the urine at infinite time)
14) Xminf (NDMAD in the body at infinite time)
15) Xmu inf (NDMAD in the urine at infinite time)
16) T1/2 (AD)(hr)
17) Clearance (AD)(L/hr)

18) dR/dT (%/hr)
19) dR/d(lnC) (%)
20) d(lnC)/dt (NDMAD)(hr-1)
21 Slope of Cp vs T ([AD] vs t) on semi-log paper
22 Slope of dXu/dt vs T(mid) vs t on semi-Log paper
23 Slope of terminal portion of Cpm vs T ([NDMAD] vs t) on semi-log paper
24) Slope of stripped portion of Cpm vs T ([NDMAD] vs t) on semi-log paper
25) Xm (bar) (Laplace domain equation for NDMAD in the body)

PROBLEM TABLE 11 - 1. Answer Pool
Numbers LaPlace Forms

a -1.33 -0.1 0 1 10 100 Xo/(s+K)
b -1.55 -0.133 0.1 1.33 12.5 120 Xo/(s+km)
c -2 -0.15 0.133 1.5 20 167 Xo/(s+kmu)
d -3.33 -0.2 0.15 2 30 200 km * Xo / ((s+km) * (s+kmu))
e -4 -0.333 0.2 3 37.5 375 kmu * Xo / ((s+km) * (s+kmu))
f -5 -0.5 0.333 4 40 425 km * Xo / ((s+km) * (s+K ))
g -6.93 -0.693 0.5 5 50 500 kmu * Xo / ((s+K ) * (s+kmu))
h -7.5 -0.73 0.693 6 55.6 630 km * Xo / ((s+K ) * (s+kmu))
i -8.25 -0.85 0.75 6.67 66.7 775 kmu*km*Xo / ((s+K ) * (s+kmu))
j -9 -0.95 0.84 7.5 75 930 kr*Xo / ((s+K ) * (s+kmu))

14.5.3 ADINAZOLAM SOLUTIONS
X ku Xu
km
Xm kmu Xmu
onse %
R vs T
60
Adinazolam metabolite
80
50
70
40
60
Response (%P-col)
30
50
40
20
30
10 10 2 10 3
2 3 4 5 6 7 8
Time (hr) Concentration (ng.mL)
AD IV Bolus - Metab
Adinazolam IV Bolus 102
10 2
101
10 1
100
10 0
0 5 10 15 20 25
0 1 2 3 4 5 6

–1 22 Slope of
1 K = 0.333hr
dX u
–1 ---------vsT( mid ) = – 0.333
2 k r = 0.133hr dt
–1
23 Slope of the terminal portion of
3 k m = 0.2hr Cp m vsT = – 0.2
–1 24 Slope of the stripped portion = -
4 k mu = 0.2hr
0.333
5 Cp 0 = 55.6ng ⁄ mL
km ⋅ X0
25 X m = ---------------------------------------
-
6. Vd = 90L ( s + K ) ( s + k mu )
7 Vd m = 50L
8 AUC = 167ng ⁄ mL ⋅ hr
2
9 AUMC = 500ng ⁄ mL ⋅ hr
10 MRT = 3.0hr
11 AUC m = 2.0mg
∞
12 X = 0
∞
13 X u = 2.0mg
∞
14 Xm = 0
∞
15 Xmu = 3.0mg
16 T1 ⁄ 2 = 2hr
17 Cl = 30L ⁄ hr
dR
18 ------- = – 7.42 %hr
dT
dR = 37.5
19 ----------------- %
d ( ln C )
( ln C ) = – 0.2hr – 1
d-----------------
20
dt
21 Slope of Cp vs T([AD] vs t) = -
0.333

Practice Exams: Section 1 : Labetalol - Section 1
14.6 Labetalol - Section 1

Saotome, et. al (J. Clin. Pcol 1993,33:979- 988)
14.6.1 LABETALOL DATA

Labetalol is a selective α- blocking and nonselective β-blocking agent used in the treatment of hypertension. It is
excreted unchanged into the urine and extensively metabolized. The metabolites are excreted into the urine and bile.
Labetalol reduces diastolic blood presure.
PROBLEM TABLE 11 - 1. P-col Resp vs Time (hrs) P-col Resp v Labetalol Conc
Pharmacological Response Profiles
Decrease in BP Time Decrease in BP Cp

(mm Hg) (hr) (mm Hg) (ng/mL)
22.2 2 14.5 100
20.3 4 16.5 160
18.5 6 19.5 275
16.6 8 22.5 525
PROBLEM TABLE 11 - 1. Data from a 200 mg IV Bolus dose (Intercept of extrapolated Metabolite data = 22.7 mg/hr)
Time Labetalol Metabolite

(mid) Excretion rate Excretion Rate
Time
(hrs) Cp t (mg/hr) (mg/hr)
0.5 364 0.5 1.82 5.1
1 331 1 1.66 8.2
2 274 1.5 9.8
4 187 2 1.37 10.6
6 128 2.5 10.7
8 88 3 10.5
4 0.94 9.5
6 0.64 7.0
8 4.9
12 2.3
18 0.74
24 0.24

14.6.2 LABETALOL QUESTIONS

From the above information find the phar- 21) Clearance (labetalol)(L/hr)
macokinetic parameters:
22) dR/dT (%/hr)
1) K (elimination rate constant of labe-
23) dR/d(lnC) (%)
talol) (hr-1 )
24) d(lnC)/dt (labetalol)(hr-1)
2) K2 (elimination rate constant of labe-
talol metabolites (hr-1 ) 25 Slope of Cp vs T ([labetalol] vs t) on
semi-log paper
3) kr (urinary excretion rate constant of
labetalol)(hr-1 ) 26 Slope of dXu/dt vs T(mid) vs t on
semi-Log paper
4) km (metabolism rate constant of labe-
talol)(hr-1 ) 27 Slope of terminal portion of Cpm vs T
([Metabolites of labetalol] vs t) on
5) kmu (urinary excretion rate constant of
semi-log paper
Metabolites of labetalol)(hr-1 )
28) Slope of stripped portion of Cpm vs T
6) kmb (biliary excretion rate constant of ([Metabolites of labetalol] vs t) on
Metabolites of labetalol)(hr-1 ) semi-log paper
7) Cp0 (IV bolus labetalol) (ng/mL) 29) Xm (bar) (Laplace domain equation for Metabolites
8) Vd (labetalol)(L.) of labetalol in the body)
9) AUC (Cp vs t for labetalol by IV bolus) 30) dXmu / dT (equation for the rate of
(ng/mL * hr) excretion of metabolites into the urine)
10) AUMC (t*Cp vs t for labetalol by IV 31) Fraction of labetalol excreted

bolus (ng/mL * hr2) unchanged.
11) MRT (labetalol)(hr) 32) Fraction of labetalol eliminated as

metabolites in the urine.
12) AUC (dXu/dt vs t(mid) for labetalol by
IV bolus) (mg) 33) Fraction of labetalol eliminated as
metabolites in the bile.
13) AUC (dXmu/dt vs t(mid) for Metabo-
lites (mg))
14) AUC (dXmb/dt vs t(mid) for Metabo-
lites (mg))
15) Xinf (labetalol in the body at infinite time (mg))
16) Xuinf (labetalol in the urine at infinite time (mg))
17) Xminf (Metabolites of labetalol in the body at infi-

nite time (mg))
18) X muinf (Metabolites of labetalol in the urine at infi-

nite time (mg))
19) X mbinf (Metabolites of labetalol in the bile at infi-

nite time (mg))
20) T1/2 (labetalol)(hr)

14.6.3 LABETALOL SOLUTIONS
X ku Xu
km
Xmf kmf Xm kmu Xmu
Labatalol
Labatalol
23
24
22
21 22
20
20
Response (mmHg)
19
Response (mmHg)
18 18
17
16 16
2 3 4 5 6 7 8 14
10 2 103
Time (hr)
Concentration (ng.mL)
Labatalol Labatalol Metabolite Labatalol

102 10 1
103
101
102 10 0
100
Excretion rate (mg/hr)
101 10-1 10 -1
Excretion Rate (mg/hr)
0 2 4 6 8 0 5 10 15 20 25 0 1 2 3 4 5 6
Time (hours) Time (hours) Tmid (hours)

–1 dR
1 K1 = 0.190hr 23 ----------------- = 4.90 %
d ( ln C )
–1
2. K2 = 0.792hr d ( ln C ) –1
24 ----------------- = – 0.190hr
–1 dt
3 k r = 0.01hr
–1
–1 25 Slope of Cp vs T = – 0.190hr
4 k m = 0.18hr
26 Slope of
–1 dX u
5 k mu = 0.38hr --------- vsT( mid ) vs ( t ) = – 0.190
dt
–1
6 k mb = 0.41hr 27 Slope of terminal portion
of Cp m vsT = – 0.190
7 Cp 0 = 400ng ⁄ mL
28 Slope of stripped portion of
8 Vd = 500L
Cp m vsT = – 0.79
9 AUC = 2105ng ⁄ mL ⋅ hr
km ⋅ X 0
10 29 X m = -----------------------------------------
-
( s + K1 ) ( s + K2 )
2
AUMC = 11072ng ⁄ mL ⋅ hr
30
11 MRT = 5.26hr X mu ( k mu ⋅ k m ⋅ X 0 ) – K2t – K1T
--------- = ---------------------------------- ( e –e )
dt ( K1 – K2 )
12 AUC = 10.5mg
31 Fraction of labetalol excreted
13 AUC = 91.2mg
10.5
unchanged: ---------- × 100 = 5.25 %
14 AUC = 98.3mg 200
∞ 32 Fraction of labetalol excreted as
15 X = 0 metabolites in urine:
∞ 91.2
16 X u = 10.5mg ---------- × 100 = 45.6 %
200
∞ 33 Fraction of labetalol eliminated as
17 Xm = 0
metabolites in bile:
∞ 98.3
18 Xmu = 91.2mg ---------- × 100 = 49.15 %
200
∞
19 Xmb = 98.3mg
20 T1 ⁄ 2 = 3.64hr
21 Cl = 95L
dR
22 ------- = – 0.93 %hr
dT

Practice Exams: Section 1 : Zidovudine Section 1
14.7 Zidovudine Section 1
14.7.1 ZIDOVUDINE DATA

Zidovudine (ZDV - formerly azidithymidine (AZT)) is used to treat HIV positive patients with AIDS and AIDS related
complex (ARC). The in vitro virustatic concentration is 250 mic/mL. While the pharmacokinetics of ZDV is complex,
we can approximate it with the following model. ZDV is excreted unchanged into the urine to UZDV. It is metabo-
lized by hepatic glucuronidation to an inactive metabolite, GZDV, and also metabolized by intracellular phosphoryla-
tion to the active metabolite, ZDV-TP. Both metabolites are excreted into the urine (UGZDV and UZDV-TP). The
anti-retroviral activity was shown in the following data:
PROBLEM TABLE 11 - 1. ZDV-TP Response vs time and response vs concentration data
Pharmacological Response Data
Concentration Activity Time Activity

ZDV-TP (ng/mL) % (min) %
100 80 0 100
90 76.8 30 100
75 68.5 60 100
50 52.3 120 92
25 24.5 240 82
360 72
480 62
PROBLEM TABLE 11 - 1. 100 mg dose ZDV given by IV Bolus to 70 KG patient
Time Cp ZDV Cpm GZDV Interval UZDV Collected Rate of AUC

(hours) (ng/mL) (ng/mL) (hrs) (mg) excretion data UGZDV (mg)
0.25 40 0-1 9.2 60
0.5 75 1-2 4.8
0.75 100 2-3 2.5
1 315 125 4-6 1
1.5 150
2 170 160
3 91 160
4 48 145
6 13 100
8 65
10 40
12 25

Please use the following nomenclature:

D = Dose of ZDV
K = elimination rate constant of ZDV
kr = excretion rate constant of ZDV
kmu1 = excretion rate constant of ZDV-TP
kmu2 = excretion rate constant of GZDV
km1 = metabolism rate constant of ZDV to ZDV-TP
km2 = metabolism rate constant of ZDV to GZDV

14.7.2 ZIDOVUDINE QUESTIONS

1) Using Laplace transforms, find the 14) What is the terminal slope (*-1) of
equation for the rate of excretion of GZDV ln(GZDV) vs t (hr^-1)?
into the urine. (For this question use the
15) What is the terminal slope (*-1) of
following answer set:
ln(dUZDV/dt) vs t (hr^-1)?
a= I only
16) What is the intercept of ZDV vs t (ng/
b= III only mL)?
c = I + II only 17) What is the intercept of dUZDV/dt vs t
(mg/hr)?
d = II + III only
18) What is the intercept of the extrapo-
e = All three
lated line from plasma GZDV vs time data
(ng/mL)?
I (kmu2*km2*D/(K-kmu2))*(exp(-K*t)) 19) What is the intercept of the extrapo-
II (kmu2*km2*D/(K-kmu2))*(exp(- lated line from dUGZDV/dt vs time data
kmu2*t)) (mg/hr)?
III -(kmu2*km2*D/(K-kmu2))*(exp(- 20) What is the Cp0 of ZDV (ng/mL)?

K*t)) 21) What is the volume of distribution of
ZDV (L)?
2) Using linear regression on the pharma- 22) What is the volume of distribution of
cological response / concentration profile, GZDV (L)?
what was the Summation of XY? 23) What is the clearance of ZDV (L/hr)?
3) What is d%R/d(lnC)(%)? 24) What is the half life of ZDV (hr)?
4) What is d%R/dt (%/hr)? 25) What is the MRT of ZDV (hr^-1)?
5) What is K (hr^-1)? 26) What is the AUC of the first trapazoid
6) What is kr (hr^-1)? of ZDV vs time (ng/mL*hr)?
7) What is km1 (hr^-1)? 27) What is the AUC(from 0 to infinity) of

the IV bolus ZDV plasma data (ng/
8) What is km2 (hr^-1)? mL*hr)?
9) What is kmu1 (hr^-1)? 28) How much ZDV is in the body at infi-
10) What is kmu2 (hr^-1)? nite time (mg)?
11) What is the terminal slope (*-1) of 29) How much GZDV is in the body at
ln(ZDV) vs t (hr^-1)? infinite time (mg)?
12) What is the terminal slope (*-1) of 30) How much ZDV-TP is in the body at
ln(ZDV-TP) vs t (hr^-1)? infinite time (mg)?
13) What is the terminal slope (*-1) of 31) How much ZDV is in the urine
ln(ZDV-TP) vs t (hr^-1)? (UZDV) at infinite time (mg)?
32) How much GZDV is in the urine
(UGZDV) at infinite time (mg)?

33) How much ZDV-TP is in the urine

(UZDV-TP) at infinite time (mg)?

14.7.3 ZIDOVULDINE SOLUTIONS
Xm1 km1 X ku Xu
km2
kmu1
Xmu1 Xm2 kmu2 Xmu2
Zidovudine Zidovudine
110 90
100 80
70
90
60
80 50
Response (% Activity)
70 40
Response (% Activity)
30
60 20
0 100 200 300 400 500
10 1 102
Time (min)
Zidovudine Zidovudine Metobolite Zidovudine Urine data

103 103 102
102 102 101
101 101
100
UZVD (mg)
0 1 2 3 4 5 6 0 2 4 6 8 10 12
10-1

0 1 2 3 4 5
Tmid (hours)

1. Answer is D - II and III 26 457.5ng ⁄ mL ⋅ hr

2 1289.2
27 952ng ⁄ mL ⋅ hr
3 40%
28 0
4 -0.08333%hr
29 0
–1
5 K = 0.630hr 30 0
6 k r = 0.125hr
–1 31 20mg
–1
32 60mg
7 k m1 = 0.25hr
33 20mg
–1
8 k m2 = 0.25hr
–1
9 k mu1 = 0.125hr
–1
10 k mu2 = 0.378hr
–1
11 0.630hr
–1
12 0.250hr
13 Skip - same question as #12
–1
14 0.25hr
–1
15 0.630hr
16 600ng ⁄ mL
17 12.6mg ⁄ hr
18 500ng ⁄ mL
19 12.6mg ⁄ hr
20 600ng ⁄ mL
21 166.7L
22 200L
23 105L ⁄ hr
24 1.1hr
25 1.6hr

Practice Exams: Section 1 : Fosinopril Section 1
14.8 Fosinopril Section 1

Kostis et al “Fosinopril: Pharmacokinetics and pharmacodynamics in congestive heart failure” Clin Pcol Ther 58(6) 660-5
(1995); Hui et al “Pharmacokinetics of fosinopril in patients with various degrees of renal function” Clin Pcol Ther 49(4) 457 -66
(1991)
14.8.1 FOSINOPRIL DATA

Fosinopril Sodium is a phosphinic prodrug of the angiotensin converting enzyme (ACE) inhibitor fosinoprilat effective
in the treatment of hypertension and chronic heart failure (CHF). The parent compound is weakly active, if at all. Its
sole metabolite, fosinoprilat, exhibits almost all of the pharmacological activity. After administration, fosinopril is
entirely converted to the active fosinoprolat by esterases in the liver. Unlike other ACE inhibitors, elimination of fos-
inoprilat is divided equally between renal and hepatic pathways (liver metabolism). The following information was
obtained from a 70 Kg male.
Wherever necessary, please use the following symbols:
Cp = plasma concentration of parent drug, fosinopril
Cpm1 = plasma concentration of metabolite, fosinoprilat.
Cpm2= plasma concentration of metabolite of fosinoplilat.
X = amount of parent compound, fosinopril, in the body
Xm1 = amount of metabolite, fosinoprilat, in the body
Xm2 = amount of metabolite of fosinoprilat in the body
Xu = cumulative amount of parent drug in urine.
Xmu1 = cumulative amount of metabolite, fosinoprilat, in urine.
Xmu2 = cumulative amount of metabolite of fosinoprilat in urine.
ku = renal excretion rate constant of parent drug in plasma.
kmu1 = renal excretion rate constant for metabolite, fosinopril, in plasma.
kmu2 = renal excretion rate constant for metabolite of fosinopril in plasma.
kf = fecal excretion rate constant of parent drug in plasma.
kmf1 = fecal excretion rate constant for metabolite, fosinopril, in plasma.
kmf2 = fecal excretion rate constant for metabolite of fosinopril in plasma.
km1 = metabolism rate constant of fosinopril in plasma.
km2 = metabolism rate constant of fosinoprilat in plasma.
K1 = elimination rate constant of parent drug in plasma = summation of all processes which remove fosinopril.
K2 = elimination rate constant of metabolite1 in plasma = summation of all processes which remove fosinoprilat.
K3 = elimination rate constant of metabolite2 in plasma = summation of all processes which remove the metabolite of fosinoprilat.

PROBLEM TABLE 11 - 1. Pharmacological Response data (Six hours after dosing with fosinopril)
Time Fall in SSBP Fall in SSBP Dose

(hr) (mm Hg) (mg Hg) (mg)
3 22 5 10
5 21 11 20
8 19 16 40
11 17 22 80
13 16
Urine Data
Plasma Data (from 20 mg Fosinopril IV bolus)
(from7.5 mg Fosinoprilat IV Bolus) (Intercept 0.855 mg/hr)
Cp
Tme (Fosinoprilat) Interval Amount (Fosinoprilat)
(hours) (ng/mL) (hr) (mg)
1 387 0-1 0.158
2 360 1-2 0.362
3 335 2-3 0.467
4 311 3-4 0.513
6 269 4-6 1.05
6 - 10 1.84
10 - 14 1.42
14 - 22 1.84
22 - 26 0.592

14.8.2 FOSINOPRIL QUESTIONS

From the parent compound, Fosinopril, ♥18) K1, the elimination rate constant of parent drug in
given by IV bolus, find the equation for: plasma , the summation of all processes which remove
Fosinopril.
♣1) X, the mass of parent drug, Fosinopril,
♠19) K2, the elimination rate constant of metabolite in
in the body
plasma , the summation of all processes which remove
♣) Xu, the mass of parent drug, Fosinopril, Fosinoprilat.
in urine.
♣3) dXu/dt, the rate of excretion of parent For fosinoprilat IV, find the value of :
drug, Fosinopril, in urine.
♥20) AUC(fosinoprilat)
♣4) Xf, the mass of parent drug, Fosino-
pril, in feces. ♥21) AUMC(fosinoprilat)
♣5) Xm1, the mass of metabolite, Fosino- ♥22) MRT(fosinoprilat)

prilat, in the body ♥23) Ke for fosinoprilat (hr-1)
♣6) Xm1u, the mass of metabolite, Fosi- ♥24) T 1 ⁄ 2 for Fosinoprilat (hr)
noprilat, in urine.
♣7) dXm1u/dt, the rate of excretion of ♥25) Cp0(fosinoprilat) for iv dose (ng/mL)
metabolite, Fosinoprilat, in urine. ♥26) Vd for Fosinoprilat (L)
♣8) Xm1f, the mass of metabolite, Fosino- ♥27) Cp of Fosinoprilat at eight hours
prilat, in feces. after the IV dose
♣9) Cp, the plasma concentration of parent
drug, Fosinopril
For fosinoprilat given as IV fosinopril,
♣10) Cpm1, the plasma concentration of dXm1/dt, find the value of :
metabolite, Fosinoprilat.
♠28) AUC(fosinoprilat)(mg)
♠29) AUMC(fosinoprilat)
Find the value of:
♠30) MRT(fosinoprilat)
♦11) dR/dT
♠31) K2 for fosinoprilat (hr-1)
♦12) dR/d(ln(Cpm1))
♠32) T ? for Fosinoprilat (hr)
♦13) d(ln(Cpm1))/dT
♠33) K1 for fosinopril (hr-1)
♥14) ku, the renal excretion rate constant of parent drug,
Fosinopril, in plasma.
♥15) km1, the metabolism rate constant of parent drug,

Fosinopril, in plasma.
♠16) kmu1, the renal excretion rate constant for metabo-

lite, Fosinoprilat, in plasma.
♠17) km2, the metabolism rate constant for the metabo-

lite of Fosinoprilat in plasma.

PROBLEM TABLE 11 - 1. Answer Pool
Minus Small Med. Large Equations More equations
A -0.037 0 1.35 155 None ((km1 X0/Vdm )/(K1-K2))(e-K2t-e-K1t )
B -0.050 0.037 5.0 232 X0e-K1t ((km1 X0/Vdm )/(K1-K2))(e-K1t-e-K2t )
C -0.074 0.06 7.4 420 (X0/Vd)e-K1t ((kmu1 X0/Vdm )/(K1-K2))(e-K2t-e-K1t)
D -0.082 0.074 8.2 840 ku X0e -K1t ((kmu1km1 X0)/(K1-K2))(e-K2t-e-K1t )
E -0.10 0.135 9.4 940 kf X0e-K1t ((kmu1km1 X0)/(K1-K2))(e-K1t-e-K2t )
F -0.135 0.5 10 5676 (k u/K1) X0(1-e-K1t) ((kmu1 X0)/(K1-K2))(e-K2t-e-K1t )
G -0.37 0.6 12 13500 (k f/K1) X0(1-e-K1t) ((kmf1km1 X0)/(K1-K2))((1-e-K2t)/K2-(1-e-K1t )/K1)
H -0.50 0.74 13.5 15700 ((km1 X0)/(K1-K2))(e-K2t-e-K1t) ((kmf1km1 X0)/(K1-K2))((1-e-K1t)/K1-(1-e-K2t )/K2)
I -0.6 0.82 15.5 18000 ((km1 X0)/(K1-K2))(e-K1t-e-K2t) ((kmu1km1 X0)/(K1-K2))((1-e-K2t )/K2-(1-e-K1t)/K1)
J -0.74 0.94 18 76700 ((kmu1 X0)/(K1-K2))(e-K2t-e-K1t) ((kmf2km1 X0)/(K1-K2))((1-e-K2t)/K2-(1-e-K1t )/K1)

14.8.3 FOSINOPRIL SOLUTIONS
ku=0
X
K1= km1
km1 K2= kmu1+km2
K3= kmu2
kmu1
Xm1 Xmu1
km2
kmu2
Xm2 Xmu2
R vs Ln(c)
Response
25
R vs T
23
20
22
Response
21
15
20
1 2
19
10
18
5
17
16
0
10 10 15
Concentration 0 2 4 6 8 10 12 14
Time (hr)
Fosinoprilat in Urine
Fosinoprilat 10
0
Excretion Rate (mg/hr)
3
10
Concentration ng/mL
-1
102
10
0 1 2 3 4 5 6 0 5 10 15 20 25
Time (hr) Time (hr)

♣1) X, the mass of parent drug, Fosinopril, in the body B - X0e-K1t

♣) Xu, the mass of parent drug, Fosinopril, in urine. A - none(no drug goes there)
♣3) dXu/dt, the rate of excretion of parent drug, Fosinopril, in urine A = none(no drug goes there)
♣4) Xf, the mass of parent drug, Fosinopril, in feces. A = none(no drug goes there)
♣5) Xm1, the mass of metabolite, Fosinoprilat, in the body H = (km1X0)/(K1-K2)(e-K2t-e-K1t)

♣6) Xm1u, the mass of metabolite, Fosinoprilat, in urine. I =
( k mu1 k m1 X 0 )  1 – e –K2t 1 – e – K1t 
--------------------------------  --------------------- – --------------------- 
( K1 – K2 )  K2 K1 
(k k X )
♣7) dXm1u/dt, the rate of excretion of metabolite, Fosinoprilat, in urine. mu1 m1 0
-{e
D = ------------------------------- –K2t
–e
– K1t
}
( K1 – K2 )
♣8) Xm1f, the mass of metabolite, Fosinoprilat, in feces. A = none(no drug goes there)
X
♣9) Cp, the plasma concentration of parent drug, Fosinopril C =  -----0- e – K1t
Vd
k X
♣10) Cpm1, the plasma concentration of metabolite, Fosinoprilat. m1 0
-{e
A = ------------------------------- –K2t
–e
– K1t
}
( K1 – K2 )V d
Find the value of:

♦11) dR/dT I = -0.6 mm Hg/hr
♦12) dR/d(ln(Cpm1)) D = 8.2 mm Hg
♦13) d(ln(Cpm1))/dT C = -0.074 hr-1

♥14) ku, the renal excretion rate constant of parent drug, Fosinopril, in plasma. A = none(no drug goes there)
♥15) km1, the metabolism rate constant of parent drug, Fosinopril, in plasma. F = 0.5 hr -1
♠16) kmu1, the renal excretion rate constant for metabolite, Fosinoprilat, in plasma. B = 0.037 hr -1
♠17) km2, the metabolism rate constant for the metabolite of Fosinoprilat in plasma. B = 0.037 hr -1
♥18) K1, the elimination rate constant of parent drug in plasma , the summation of all processes which remove Fosinopril. F = 0.5 hr -1
♠19) K2, the elimination rate constant of metabolite in plasma , the summation of all processes which remove Fosinoprilat. D = 0.074 hr -1
For fosinoprilat IV, find the value of :

♥20) AUC(fosinoprilat) F = 5676 ng/mL
♥21) AUMC(fosinoprilat) J = 76700 mg/mL*hr2

♥22) MRT(fosinoprilat) H = 13.5 hr

♥23) Ke for fosinoprilat (hr-1) D = 0.074 hr -1

♥24) T 1 ⁄ 2 for Fosinoprilat (hr) E = 9.4 hr
♥25) Cp0(fosinoprilat) for iv dose (ng/mL) C = 420 ng/mL

♥26) Vd for Fosinoprilat (L) J = 18 L
♥27) Cp of Fosinoprilat at eight hours after the IV dose B = 232 ng/mL
For fosinoprilat given as IV fosinopril, dXm1/dt, find the value of :

♠28) AUC(fosinoprilat)(mg) F = 10 mg
♠29) AUMC(fosinoprilat) A = 155 mg*hr
♠30) MRT(fosinoprilat) I = 15.5 hr
♠31) K2 for fosinoprilat (hr-1) D = 0.074 hr -1

♠32) T ? for Fosinoprilat (hr) E = 9.4 hr
♠33) K1 for fosinopril (hr-1) F = 0.5 hr -1

14.9 Omeprazole
14.9.1 OMEPRAZOLE DATA

Omeprazole (mw: 345.42) is a gastric proton-pump inhibitor which decreases gastric acid secretion. It is effective in
the treatment of ulcers and esophageal reflux. In normal patients, 20% of the omeprazole is excreted into the feces and
80% of the omeprazole dose is excreted as an inactive metabolite into the urine. In the study by Anderson, et. al., eight
patients were given 20 mg, IV bolus doses of omeprazole. The patients had a mean body weight of 70 kg. Blood and
urine were collected at various intervals throughout the study and the following data was obtained:
TABLE 14-2 Pharmacological Response
% Acid Secretion % Acid Secretion Concentration

Inhibition Time (min) Inhibition (ng/mL)
100 120 74 1
100 240 62 .6
75 330 56 .5
63 360 47 .35
56 375 27 .15
50 390
25 450
10 570
8 600
0 720
TABLE 14-3 Plasma profile of parent and urine profile of metabolite
Intercept = 4 mg/hr
Parent Compound AUMCmet = 96 mg*hr
Urine Collection Metabolite

Time (hr) Cp (ng/mL) Interval (hr) collected (mg)
0.5 336 0-1 1.19
1 205 1-2 2.07
2 75 2-3 2.10
3 28 3-5 3.44
4 10 5-7 2.38
7-9 1.62
9 - 11 1.08
11 - 13 0.72
13 - 15 0.48
16 - 20 0.44

14.9.2 OMEPRAZOLE QUESTIONS

Using LaPlace transforms, from Omeprazole, given by IV bolus, find the equation
for:
1. ♣1) X, the mass of Omeprazole in the body
2. ♣) Xu, the mass of Omeprazole in urine.
3. ♣) dXu/dt, the rate of excretion of Omeprazole in urine.
4. ♣) Xf, the mass of Omeprazole in feces.
5. ♣) Xm, the mass of metabolite of Omeprazole in the body
6. ♣) Xmu, the mass of metabolite of Omeprazole in urine.
7. ♣) dXmu/dt, the rate of excretion of metabolite of Omeprazole in urine.
8. ♣) Xmf, the mass of metabolite of Omeprazole in feces.
9. ♣) Cp, the plasma concentration of parent drug, Omeprazole
10. ♣) Cpm, the plasma concentration of metabolite of Omeprazole.
Find the value of:
11. ♦) dR/dT = slope of the Pharmacological response vs. time profile (% / hr)
12. ♦ ) dR/d(lnC) = slope of the Pharmacological response vs concentration profile (%)
13. ♦) d(lnC)/dt = slope of the concentration vs time profile (hr-1 )

14. ♥♠ ) kr = urinary excretion rate constant Omeprazole (hr-1 )
15. ♥♠) kf = fecal excretion rate constant Omeprazole (hr-1 )
16. ♥♠) km = rate of metabolism of Omeprazole in the body (hr-1 )
17. ♥♠) K1 = elimination rate constant of Omeprazole in the body; the summation of all of the ways that it
is removed from the body. (hr-1 )
18. ♥♠) T1/2 of Omeprazole in the body (hr)
19. ♥♠) X0 = Mass of Omeprazole in the body at time 0 (mg)
20. ♥♠) Xinf = Mass of Omeprazole in the body at time infinite time (mg)
21. ♥♠) Xuinf = Mass of unchanged Omeprazole in the urine at infinite time (mg)
22. ♥♠) Xfinf = Mass of unchanged Omeprazole in the feces at infinite time (mg)
23. ♥♠) V = Volume of distribution of Omeprazole (L)
24. ♥♠) Cp0 = Concentration of Omeprazole in the body at time 0. (mic/L)
25. ♥♠) AUCiv = Area under the plasma concentration of Omeprazole vs time curve of the IV
dose (mic/L*hr)
26. ♥♠) First trapazoid of the AUCiv (mic/L*hr)
27. ♥♠) Last trapazoid of the AUCiv (mic/L*hr)
28. ♥♠) AUMCiv = Area under the first moment of the plasma concentration of Omeprazole vs
time curve of IV dose (mic/L*hr2 )
29. ♥♠) MRTiv = Mean Residence time of Omeprazole given as the IV dose (hr)
30. ♥♠) Xm = Mass of metabolite in the body at time = 0 (mg)

31. ♥♠) Xminf = Mass of the metabolite in the body at infinite time. (mg)
32. ♥♠) Vm = Volume of distribution of the metabolite in the body (L)
33. ♥♠) Cpm = Concentration of metabolite in the body at time = 0 (mic/L)
34. ♥♠) AUCmet = Area Under the Curve of the metabolite excretion rate vs time profile (mg)
35. ♥♠) Xmu0 = Mass of metabolite in urine at time = 0 (mg)
36. ♥♠) Xmuinf = Mass of metabolite in urine at time = infinity (mg)
37. ♥♠) Xmf0 = Mass of metabolite in feces at time = 0 (mg)
38. ♥♠) Xmfinf = Mass of metabolite in feces at time = infinity (mg)
39. ♥♠) Kmu = Rate constant of excretion of metabolite into urine (hr-1 )
40. ♥♠) Kmf = Rate constant of excretion of metabolite into feces (hr-1 )
TABLE 14-4 Omeprazole Answer Pool
Minus Small Med Large Equations More Equations
A -0.8 0 1 100 None km X0 –K 2 t – K1 t

- (e
--------------------------------- –e )
( K 1 – K 2 )V dm
B -1 0.1 2 147 – K1 t km X0 –K 1 t – K2 t
X0 e - (e
--------------------------------- –e )
( K 1 – K 2 )V dm
C -2 0.2 4 210 X 0  –K 1 t
 ------ k mu X 0 –K 2 t – K1 t
- e - (e
--------------------------------- –e )
 Vd ( K 1 – K 2 )V dm
D -4 0.3 8 223 ku X0 e
–K 1 t k mu k m X 0 – K 2 t – K1 t
----------------------- (e –e )
( K1 – K 2 )
E -8 0.4 10 372 kf X0 e
– K1 t k mu k m X 0 – K 1 t – K2 t
----------------------- (e –e )
( K1 – K 2 )
F -10 0.5 16 444 ku 

 ------ –K1 t k mu X 0 –K 2 t – K1 t
X (1 – e ) ----------------------- (e –e )
K  0 ( K1 – K 2 )
1
G -16 0.6 20 556 kf 

 ------ –K1 t
k mf k m X 0  1 – e – K2 t  1 – e – K 1 t
 K  X0 ( 1 – e )
-----------------------  --------------------- –  ---------------------
1 ( K1 – K 2 )  K 2   K 1 
H -20 0.7 25 643 k m X0 –K 2 t – K1 t k mf k m X 0  1 – e – K1 t  1 – e – K 2 t

----------------------- (e –e )  --------------------- –  ---------------------
( K1 – K 2 ) -----------------------
( K1 – K 2 )  K 1   K 2 
I -25 0.8 36 756 k m X0 –K 1 t – K2 t k mu k m X 0  1 – e – K2 t  1 – e – K 1 t

----------------------- (e –e ) -----------------------  --------------------- –  ---------------------
( K1 – K 2 ) ( K1 – K 2 )  K 2   K 1 

Minus Small Med Large Equations More Equations
J -36 0.9 44 893 k mu X 0 –K2 t – K1 t k mu k m X 0  1 – e – K1 t  1 – e – K 2 t

----------------------- (e –e )
( K1 – K 2 ) -----------------------  --------------------- –  ---------------------
( K1 – K 2 )  K 1   K 2 
A Missing Information. Can not answer question with information available

14.9.3 OMEPRAZOLE SOLUTIONS
kf
Xf X
km
kmu
Xm Xmu
80 80
70 70
-1 0
60 60
Response
Response
50 50
40 40
30 30
20 20
320 340 360 380 400 420 440 460 10
Concentration 10
Time (min)
10
10
Concentration
Concentration
10 10
10
0 2 4 6 8 10 12 10
0 5 10 15 20
Time (hr) Time (hr)

– K1 t
1. (B) X = X0 e
2. (A) X u = 0 See model.
dX u
3. (A) --------- = 0 See model.
dt
k
Xf =  ------f  X 0 ( 1 – e
–K 1 t
4. (G) )
K 
1
km X0 –K 2 t – K1 t
5. (H) X m = ----------------------- (e –e )
( K1 – K 2 )
k mu k m X 0  1 – e – K2 t  1 – e – K1 t
6. (I) X mu = -----------------------  --------------------- –  ---------------------
( K 1 – K2 )  K2   K1 
dX mu k mu k m X 0 – K2 t – K 1 t
7. (D) ------------- = ----------------------- (e –e )
dt ( K 1 – K2 )
8. (A) X mf = 0 See model.
X
C p =  ------0- e
–K 1 t
9. (C)  Vd
km X 0 – K2 t –K 1 t
10.(A) -(e
C pm = --------------------------------- –e )
( K 1 – K 2 )V dm
dR – 0.4% – 25%
11.(I) ------- ≅ ------------------ ≅ -------------- Estimate from graph. Between 20-80% of maximal
dt minute hr
response ONLY!
dR 74%-57% 17%
12.(H) --------------- = ---------------------------------------------- = ------------- ≅ 25% Points taken from sample graph.
d ln C p ng ng 0.693
ln 1.0 ------ – ln 0.5 ------
ml ml
d ln C p dR d ln C – 25% 1 –1
13.(B) --------------- = ------- × ---------------p = -------------- × ----------- = – 1 hr
dt dt dR hr 25%
14.(A) kr = 0 See model.
∞ –1
Xf K 1 4mg ⋅ 1hr
15.(C) k f = -------------
- = ----------------------------- = 0.2hr
–1
Also, kf is 20% of K1 , or 20% of 1hr-1 =
X0 20mg
0.2hr-1
–1 –1 –1
16.(I) k m = K 1 – k f = 1hr – 0.2hr = 0.8hr if you have k f .or
∞ –1
X mu K 1
k m = ---------------- = 16mg ⋅ 1hr = 0.8hr – 1
-------------------------------- . Also, km is 80% of K1 , or 80% of 1hr-1 =
X0 20mg
0.8hr-1
– d ln C –1
17.(A) K 1 = ------------------p = 1hr
dt
18.(H) t 1 ⁄ 2 = 0.693
------------- = 0.693 → 0.7hr
K1
19.(G) X 0 = 20mg Read introduction.
20.(A) X inf = 0 See model.
21.(A) Xu ( inf ) = 0

20
22.(C) X f ( inf ) = --------- × 20mg = 4mg 20% of parent excreted in feces (read introdction).
100
23.(I) Dose- ≈ -----------------

V d = ------------ 20mg ≈ 20 , 000µg- ≈ 36L
------------------------
C p0 ng µg
556 -------- 556 ------
mL L
24.(G) ng- ≈ 556 µg

C p0 ≈ 556 ------- ------ From graph.
mL L
C p ( n ) + C p ( n + 1 ) C p ( last ) C p0
25.(G) AUC IV = ∑ 
---------------------------------------
2 
∆t + ------------------
K1
or AUC IV = --------
K1
-
AUC IV =  ------------------------ × 0.5 +  ------------------------ × 0.5 +  --------------------- × 1 +  ------------------ × 1 +

556 + 336 336 + 205 205 + 75 75 + 28
or
2 2 2 2
 28 µg ⋅ hr
------------------ × 1 + ------ = 578.75 → 556 -----------------
+ 10 10
 2  1 L
ng
556 --------
mL = 556 µ
AUC IV = ----------------- ⋅ hr
-------------
1hr L
26.(D)  556 + 336- × 0.5 = 223 µg

----------------------- ⋅ hr-
----------------
 2  L
10 µg ⋅ hr
27.(E) ------ -----------------
1 L
tn Cp (n ) + tn + 1 Cp (n + 1 ) C p ( last ) tlast C p ( last )
 -------------------------------------------------------
- ∆t + ------------------
28.(G) AUMC IV = ∑  2  2
+ ----------------------------
K1
( K1 )
( 556 ) + 0.5 ( 336 -) × 0.5 +  0.5

AUMC IV =  0-------------------------------------------- ( 336 ) + 1 ( 205 ) × 0.5 +  1-------------------------------------
--------------------------------------------- ( 205 ) + 2 ( 75 ) × 1 +
 2   2   2 
2
( 75 ) + 3 ( 28 )
 2---------------------------------- 3 ( 28 ) + 4 ( 10 ) 10 4 ( 10 ) µg ⋅ hr
× 1 +  ---------------------------------- × 1 + ------ + -------------- = 541.75 → 556 -------------------
 2   2  2 1 L
1
2
556 µg ⋅ hr
-------------------
29.(A) MRT IV AUMC L
= ------------------ ≈ ----------------------------- ≈ 1hr or 1 = -------------
MRT IV = ------ 1 - = 1hr
556 µg ⋅ hr-
AUC K1 –1
---------------- 1hr
L
30.(A) Xm 0 = 0 See model.
31.(A) X m ( inf ) = 0 See model.
32.(A) V dm = Can not determine from information given. Need C pm information.
33.(A) C pm0 = 0 See model.
∑ Xmu
80
34.(F) AUC met = = --------- × 20mg = 16mg . AUC is equal to all drug which goes
100
through compartment, which is 80% of the 20 mg dose, or 16 mg (read intro-
duction).
35.(A) X mu0 = 0 See model.
36.(F) 80- × 20mg = 16mg
X mu ( inf ) = -------- 80% of the 20 mg dose is found as metabolite in
100
urine (Read introduction).
37.(A) X mf0 = 0 See model.
38.(A) X mf ( inf) = 0 See model.

39.(C) k mu = K 2 = 0.2hr –1 = is k small from urine data graph because k l arg e ≅ 1hr
–1
which is K1 .
40.(A) K m f = 0 See model.

14.10 EXP3312, an Experimental Drug

Wong N, Wong P. (J Pharm Pharmacol 1996; 48: 492-497) investigated the phar-
macological and pharmacokinetic response of EXP3312
14.10.1 EXP3312 DATA
EXP3312 is a non-peptide angiotension II AT1-receptor antagonist which has

potential as an oral hypertensive drug. EXP3312 a pro-drug is metabolized to an
active metabolite M1. Experiments with rats show M1 is the active drug. As with
all angiotension II antagonists EXP3312 blocks the renin-angiotension system.
EXP3312 is a synthesized analog of Losartin, but EXP3312 has greater oral
hypotensive potency and has promise in future treatment of human renal hyperten-
sion. EXP3312 is still an experimental drug without all pharmacological responses
having been explored. However, we may assume the drug is completely metabo-
lized to the active metabolite (M1). Thereafter, the active metabolite (M1) is
excreted unchanged in the urine.
The following pharmalogical data was obtained using pithed (spinal tap) rats with
an average weight of 350 g. The concentration of drug in each rat is based on aver-
age weights of the rats. The measured responses of decrease in mean arterial pres-
sure (MAP decrease) are shown below.The researchers supplied graphical data of
mean arterial pressure in conscious renal hypertensive rats. M1 metabolite was
measured and the results are also shown in the table below.
TABLE 14-5
Response (mm Hg) M1 administration (mg/kg) Response (mm Hg) Time (hr)
(MAP) decrease I.V. bolus (MAP) decrease
25 0.01 60 0
36.5 0.03 57.4 1
48.5 0.1 54.7 2
59 0.3 49.3 4
44.5 6

The parent compound EXP3312 and metabolite M1 levels were measured in the
plasma over time. The data obtained from the active M1 metabolite and the inac-
tive partent drug EXP3312 are shown below. The standard dose for each rat was
0.3mg/kg.
TABLE 14-6
EXP3312 M1
time (hr) Cp (mic/mL) Cp (mic/mL)
0.15 0.32
0.3 0.59
0.5 0.4
1 0.26 1.34
2 0.11 1.61
3 0.045
4 1.26
6 0.81
10 0.3
12 0.18
I = 3.81 mic/mL
Use the following data was obtained when an intravenous infusion of a different
dose was given to an average rat over 45 minutes.
TABLE 14-7
time (hr) Plasma concentration

(mic/mL)
0.25 0.139
0.5 0.26
0.75 0.35
1 0.29
2 0.12
3 0.05

14.10.2 EXP3312 & M1 QUESTIONS:

Using the information given find the pharmacokinetic parameters (CHECK
YOUR UNITS!!!!!!):
1. dR/dt of M1 active metabolite (mmHg/hr)
2. dR/d(lnCp) active metabolite (mmHg)
3. d(lnCp)/dt of M1active metabolite (hr-1)
4. The slope of Cp vs: t of EXP3312 on semi-log paper (hr-1)
5. The slope of terminal portion of dXmu/dt vs: t (mid) on semi-log paper (hr-1)
6. The slope of stripped portion of Cpm vs: t or (Concentration of M1 vs: t) on semi-log paper
(hr-1)
7. The equation for X in the body.
8. The equation for Xm or M1 in the body.
9. K1 (elimination rate constant of EXP3312) (hr-1)
10. ku (urinary excretion rate constant of EXP3312) (hr-1)
11. km (metabolism rate constant of M1 (hr-1)
12. kmu (urinary excretion rate constant of M1 (hr-1)
13. Cp0 (Initial IV bolus concentration of EXP3312) (mic/ml)
14. Vd of EXP3312 (L)
15. Vdm of M1 (L)
16. AUC (Cp vs: t for EXP3312 by IV bolus) (mic/mL*hr))
17. AUMC (t*Cp vs: t for EXP3312 by IV bolus) (mic/mL* hr2))
18. MRT for EXP3312 (hr)
19. AUC (dXu/dt vs: t (mid) for EXP3312 by IV bolus) (mg)
20. AUC (dXmu vs: t (mid) for M1) (mg)
21. X0 (EXP3312 in the body at time zero) (mg)
22. Xmu 0 (M1in the urine at time zero) (mg)
23. Xm0 (M1 in the body at time zero) (mg)
24. X at 2hr (EXP3312 in the body at 2 hr.) (mg)
25. Xm at 2hr (M1 in the body at 2 hr.) (mg)
26. Xinf (EXP3312 in the body at infinite time) (mg)
27. Xuinf (EXP3312 in the urine at infinite time) (mg)
28. Xminf (M1in the body at infinite time) (mg)
29. T1/2 (EXP3312) (hr)
30. Clearance of EXP3312 (L/hr)
EXP3312 Infusion Questions:

31. K (elimination rate constant of EXP3312) (hr-1)

32. T1/2 (EXP3312) (hr)
33. Volume of distribution (L/kg)
34. Clearance (L/hr/kg)
35. How long will it take to reach 95% steady state? (hr)
36. Q (infusion rate) (mg/hr)
37. Find the plasma concentration if the infusion in Table 14-7 on page 58 was discontinued at 5
hours instead of 45 minutes. (mic/mL)
38. Find the time need for the concentration to drop to 0.23 mic/mL after the infusion in question 37
is discontinued (hours).
39. Determine the new infusion rate necessary to maintain a plasma concentration of Cpss 1.0 mic/
mL of the average rat. (mg/hr)
40. Find a loading dose for the average rat which would give the Cpss of 1.0 mic/mL immediately
(mg)

TABLE 14-8 Answer Pool
Minus Small Big Bigger Equations Equations

ones ones ones ones
A -0.121 0 0.55 1.05 None km X0 – K2 t –K 1 t
---------------------------------- (e –e )
( K 1 – K 2 )Vd m
B -0.26 0.019 0.62 1.15 –K 1 t km X0 – K1 t –K 2 t

X0 e ---------------------------------- (e –e )
( K 1 – K 2 )Vd m
C -0.391 0.039 0.72 1.32 X0  –K1 t k mu X 0

 ------
- e - (e
---------------------------------
– K2 t
–e
–K 1 t
)
 Vd ( K 1 – K 2 )V dm
D -0.567 0.063 0.80 1.69 –K 1 t k mu k m X 0 –K 2 t – K1 t

kuX 0 e ----------------------- (e –e )
( K 1 – K2 )
E -0.621 0.105 0.83 2.63 – K1 t k mu k m X 0 –K 1 t – K2 t

kf X0 e ----------------------- (e –e )
( K 1 – K2 )
F -0.866 0.146 0.866 3.5 ku 

 ------ X (1 – e
– K1 t
)
k mu X 0
----------------------- (e
– K2 t
–e
– K1 t
)
K  0 ( K 1 – K2 )
1
G -1.112 0.169 0.94 4.17 kf 

 ------ X (1 – e
– K1 t
) k mf k m X 0  1 – e –K 2 t  1 – e –K 1 t
K  0 -----------------------  --------------------- –  ---------------------
1 ( K1 – K 2 )  K 2   K1 
H -1.981 0.26 0.95 4.83 km X0

----------------------- (e
–K2 t
–e
–K 1 t
) k mf k m X 0  1 – e –K 1 t  1 – e –K 2 t
( K1 – K 2 ) -----------------------  --------------------- –  ---------------------
( K1 – K 2 )  K 1   K2 
I -2.63 0.42 0.96 7.2 km X0

----------------------- (e
–K1 t
–e
–K 2 t
) k mu k m X 0  1 – e –K 2 t  1 – e –K 1 t
( K1 – K 2 ) -----------------------  --------------------- –  ---------------------
( K1 – K 2 )  K 2   K1 
J -3.71 0.48 0.99 10.1 k mu X 0 – K2 t –K 1 t

----------------------- (e –e ) k mu k m X 0  1 – e –K 1 t  1 – e –K 2 t
( K1 – K2 ) -----------------------  --------------------- –  ---------------------
( K1 – K 2 )  K 1   K2 
This exam is given early at the request of those students who had conflict with the time agreed upon. They signed a
document stating that they would not share their experience with anyone under pain of prosecution for adademic mis-
conduct which will result minimally in an “F” for the course. You also must sign this document.
I ___________________________________________ did not comunicate in anyway anything at all regarding this
exam nor give or receive any assistance during the exam upon my honor as a health professional and under pain of
prosecution for adademic misconduct.
Signed__________________________________________________________Date__________________

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CHAPTER 14 Practice Exams: Section 1

Author: Michael Makoid

You are encouraged to work out the exams under

Basic Pharmacokinetics REV. 99.4.25 14-1

ate a model, develop equations for the model, graph

Do not just look at the graphs and the answers and

Basic Pharmacokinetics REV. 99.4.25 14-2

14.1 Nifedipine - Section 1

14.1.1 NIFEDIPINE DATA

Fall in Diastolic Fall in Diastolic

PROBLEM TABLE 11 - 1. Nifedipine IV Bolus Profile

Cp Cm1 Xm1f Xm1u Xm2f Xm2u

Basic Pharmacokinetics REV. 99.4.25 14-3

14.1.2 NIFEDIPINE QUESTIONS

Basic Pharmacokinetics REV. 99.4.25 14-4

Negative Numbers Small Numbers Big Numbers

Basic Pharmacokinetics REV. 99.4.25 14-5

14.1.3 NIFEDIPINE SOLUTIONS

Graph #3 Nifedipine IV Bolus Graph #4

Basic Pharmacokinetics REV. 99.4.25 14-6

8. T 1 ⁄ 2 = 1.85 hr from graph #3

10. Xinf = 0 from pkin description

11. X u ( inf ) = 0 from pkin description

12. X f ( inf ) = 0 from pkin description

14. 295mic ⁄ L Cp0 extrapolated back to t = 0 obtained from graph #3

Σ { 434 + 204.6 + 96.7 + 45.7 + 38.9 } mcg

Basic Pharmacokinetics REV. 99.4.25 14-7

 T 0 ⋅ C p o + T1 ⋅ C p1 T1 ⋅ C p1 + T 2 ⋅ C p 2 T2 ⋅ C p2 + T3 ⋅ C p3 T 3 ⋅ C p 3 + T last ⋅ C p last T last ⋅ C p last Cp last 

20. X m1 ( o ) = 0 from pkin description

21. X m1 ( inf ) = 0 from pkin description

22. Vm1 = 170L

23. C m1 ( 0 ) = 0 from pkin description

Basic Pharmacokinetics REV. 99.4.25 14-8

24. AUC met = 2100mic ⁄ L ⋅ hr

PROBLEM TABLE 11 - 1. Nifedipine Data

25. X m1u ( 0 ) = 0 from pkin description

26. X m1u ( inf ) = 15.1mg given in data

27. X m1f ( 0 ) = 0 from pkin description

28. X m1f ( inf ) = 3.6mg given in data

k m1u Xm1u k m1u

Basic Pharmacokinetics REV. 99.4.25 14-9

33. X m2 ( 0 ) = 0 from pkin description

34. X m2 ( inf ) = 0 from pkin description

35. C m2 ( inf ) = 0 from pkin description

36. X m2u ( 0 ) = 0 from pkin description

37. X m2u ( inf ) = 5.0mg given in data

38. X m2f ( inf ) = 1.3mg given in data

–1 k m2u k m2u X m2u 5.0mg

–1 k m2f k m2f Xm2f 1.3mg -

Basic Pharmacokinetics REV. 99.4.25 14-10

14.2 Enalapril - Section 1

14.2.1 ENALAPRIL DATA

Fall in SSBP Time (hr) after Fall in SSBP

PROBLEM TABLE 11 - 1. Enalapril - Section 1 IV Bolus Profile from a 5 mg dose

Cumulative Cumulative Cumulative

Basic Pharmacokinetics REV. 99.4.25 14-11

PROBLEM TABLE 11 - 1. Enalapril Answer Pool

Negative Small Small Medium Large

Equation Answer Pool:

k mu k m Xo 1 – e – K2t 1 – e – K1t ( k mf k m Xo ) 1 – e –K2t 1 – e – K1t

Basic Pharmacokinetics REV. 99.4.25 14-12

14.2.2 ENALAPRIL QUESTIONS

13) d(ln(C))/dT 29) Cp vs T(first trapazoid only)