Pharmacokinetics of chlorpromazine after single and

chronic dosage

Plasma concentrations of chlorpromazine and its sulfoxide were measured aer single
intramuscular, single oral, and multiple oral doses of chlorpromazine. In four out of nine
patients, intramuscular doses gave stable chlorpromazine plasma levels which were
maintained for 12 hr or longer. Chlorpromazine sulfoxide was found in plasma from all
patients aer oral doses but not after intramuscular doses, whieh indicates that
suljxidation took place presystemically. The biologie availability of single oral doses
relative to single intramuscular doses rangedfrom 10 to 69%, and was on average 32%.
After 33 days of oral dosing, the plasma levels of chlorpromazine were on average 37%
lower than might have been predietedfrom the single oral dose eurves. This was not due
to decreased biologie t! of ehlorpromazine, but apparently to a decrease in the biologie
availabi/ity by oral administration, possibly by increased presystemic metabolism.

Svein G. Dahl, Ph.D., and Roald E. Strandjord, M.D. Oslo, Nonvay

Institute of Pharmacology and Gaustad Hospital, University of Oslo

Techniques for assay of plasma levels have
now been developed for several neuroleptic
drugs. Monitoring of neuroleptic drug concen-
trations in plasma will, however, be of limited
clinical usefulness until more knowledge is
available on the relationship between plasma
levels and effects, and on the pharmacokinetics
of these drugs and their metabolites. The
phenothiazines are converted to several differ-
ent metabolites, some of which are phar-
macologically active, but it is still not clear
which metabolites have both pharmacodynamic
and pharmacokinetic properties such that they
Supported by Grant B 0106.4033 from the Royal Norwegian
Council for Scientific and Industrial Research, and by grants from
the Norwegian Drug Monopoly, the Jacob Aall Foundation, and
Anders Jahre's Foundation for the Promotion of Science.
Received for publication April 12, 1976.
Accepted for publication Nov. 20, 1976.
Reprint requests to: Dr. S. G. Dahl, Institute of Medical Biology.
University of Trams\'!, N-9001 Trams\'!, Norway.
may contribute to the effects of the drug in pa-
tients.
Although more than 30 metabolit es of chlor-
promazine have been identified,27 the plasma
levels of unchanged chlorpromazine correlate to
peripheral physiologic effects like pupil width,
salivary secretion, and sweat gland activity in
patients. 2t The antipsychotic effect of the
neuroleptic drugs seems to be related to their
ability to block dopamine receptors in the cen-
tral nervous system,26 wh ich is followed by in-
creased dopamine turnover in the brain. lt has
been demonstrated that the striatallevels of the
dopamine metabolite homovanillic acid in
chlorpromazine-treated rats correlate to the
chlorpromazine concentration in the brain. 30
Some clinical studies have indicated that there
is a relations hip between the plasma levels of
chlorpromazine and the outcome of the treat-
ment of psychosis, 2, 18, 19 but others have found
no such relationship.14

437
438 Dahl and Strandjord Clinical Pharmacology
and Therapeutics

Table I. Age, body weight, and area under plasma concentration curves*
Area under CPZSO
Area under CPZ curve Area under CPZSO curve curve/area
(ng hr/ml) (ng hr/ml) under CPZ curve

Body A o- oo , Ao-~, A~~12' A 0-36, A~;;12' Single Multiple

Age wt single single multiple single multiple oral oral
Subject (yr) (kg) im dose oral dose oral dosing oral dose oral dosing dose dosing

I 59 92 764(33) 1,055(25) 814 157 222 0.15 0.27

2 47 74 836(30) 811(40) 331 131 129 0.16 0.39
3 29 55 I ,577( 18) 556(16) 478 40 90 0.07 0.19
4 50 79 1,915(41) 1,502(29) 1,487 333 351 0.22 0.24
5 51 74 1,959(46) 993(33) 417 109 90 0.11 0.22
6 18 83 I ,288( 19) 265(14) 186 130 76 0.49 0.41
7 58 58 1,666(64) 835(38) 348 91 154 0.11 0.44
8 43 82 1,676(48) 688(63) 344 75 111 0.11 0.32
Mean 44 75 1,460 838 551 133 153 0.18 0.31
*The area extrapolated from 48 hr to infinity is given in parentheses as pereent of the tOlal area. for the chlorpromazine curves after single
doses.

plasma levels seem to be generally higher in

Special abbreviations used
total area under the plasma concen-
tration curve after a single dose
A O- T area under the plasma concentration
curve from zero to time T after a
single dose
ASS
0-12 area under the plasma concentration
curve in one dosage interval,
which was 12 hr, after repeated
dosing
plasma concentration measured at
time T after a single dose
Cl total clearance
CPZ chlorpromazine
CPZSO chlorpromazine sulfoxide
o c1uded that chlorpromazine accelerates its own
administered dose
F biologie availability
fraction of intramuscular dose that
reaches systemic circulation as
unmetabolized drug
fraction of oral dose that reaches
systemic circulation as un-
metabolized drug
tt biologie half-life
V apparent volume of distribution
Q hepatic blood flow rate
Some studies have suggested that in addition
to unchanged chlorpromazine, the 7-hydroxy
metabolite also contributes to the clinical effect
of the drug. 15 , 20 Another metabolite, chlor-
promazine sulfoxide, is considered c1inically
inactive. 7 The plasma levels of the sulfoxide
and the ratio of sulfoxide to chlorpromazine
patients c1assified as "nonresponders" than in
the "responders" to chlorpromazine treat-
me nt. 15. 20, 22
A decrease in the plasma levels of unchanged
chlorpromazine has been observed after about 2
wk of oral dosing,21, 24 and induction of drug
metabolizing enzymes in the liver or in the gut
was suggested as an explanation. 21 It was later
demonstrated that the fall of chlorpromazine
plasma levels during the first weeks of treat-
ment was accompanied by a shortening of the
half-life of antipyrine. 14 It was therefore con-
metabolism by inducing liver microsomal ox-
idizing enzymes.
Chlorpromazine is almost completely me-
tabolized in the body, and less than 1% of
the dose is excreted as unchanged drug in the
urine. 11 Where the metabolism takes place has
not, however, been definitely located. It has
been suggested that chlorpromazine is partially
metabolized during absorption from the gas-
trointestinal tract, and chlorpromazine sulf-
oxide was suggested as a possible product of
such a process. 11 A different ratio of the conju-
gated to unconjugated metabolites in the urine
has been observed after intramuscular and oral
doses of chlorpromazine,l1 and it was later
pointed out that this could be explained by a
first-pass effect in the liver by oral dosing. 10
Vo/ume 2/ Chlorpromazine kinetics ajier single and chronic dosage 439
Number 4

PATIENT 1
200 r S,ngle doses MulI'ple oral dos,ng . 100 mg , 2
50"'g ,m CPZ CPZ
:: WO L 100 mg ora lly -<0 CPZ CPZSO
E : 0-<> CPZSO

0\
50 '-
C

c

. ..
o
~ 20r
~ ~} ~
c 10 P \
e f"
.'0
b
'- , t
o

~ 5- o
:'"
Oay Oay Oay 33
2-
151' '" I I I
8
-L -L
l' t. , I ! I

o
! , , I I! ,
I "
6 12 24 36 12 12 o 6 12 24 36 48
Time aller dose (hr)

Fig. l. Plasma concentrations of chlorpromazine (CPZ) and chlorpromazine sulfoxide (CPZSO)

after single and multiple doses (Patient I). CircIes and triangles represent the mean of two determi
nations.

The elimination rate of drugs which are
metabolized in the liver may depend on the
metabolizing activity of the liver, drug binding
in the blood, and hepatic blood ftow. 3 1 It is not
clear which factors are ratelimiting in the
elimination of chlorpromazine and its active
metabolites, and how the elimination is
inftuenced by diseases causing changes in the
liver enzyme activity, the cardiac output, or the
binding of chlorpromazine and its metabolites
in blood and tissues.
This study was carried out 10 gel information
on which parameters are the most important in
determining the pharmacokinetics of chlor
promazine in man, and how these parameters
vary between individuals and during their
treatment.
Methods
Subjects. The head psychiatrist of the hos
pital departments in which this study was
conducted selected 15 female ps ychiatric in
patients for the study. After having been in
formed about the aim of the study and the pro
tocol, nine patients agreed to take part, but one
was later withdrawn. The age and body weight
of the eight subjects are given in Table I. The
patients had all been in the hospital for 1 yr or
more, and had been treated with various
neuroleptics. Patients 1 and 2 received metho
trimeprazine, 200 mg once daily; Patient 3,
ftufenazine enantate, 50 mg intramuscularly
every third week; Patients 4, 5, 6, and 8, flu
pentixol in daily doses ranging from 3 to 6 mg;
and Patient 7, haloperidol , 6 mg daily. All sub
jects were somatically healthy. Electrocardio-
gram, hemoglobin, serum creatinine, alkaline
phosphatases , bilirubin, serum proteins , and
serum cholesterol were controlled before and
after the study.
Experimental design. AU medication was
withdrawn 4 wk prior to the single intramuscu-
lar dose of chlorpromazine, and no other drugs
were given during the study. Patient 3 received
the last ftufenazine dose 7 wk before the study.
The tablets and the solution for injection con
tained chlorpromazine Hel. The dos es and
plasma concentrations are, however , given here
as the equivalent amount or concentration of
free base. The tablets were taken during or
shortly after a me al of sandwiches, milk, and
coffee, according to the hospital routine . About
3 1h hr after administration of the single dose
and the morning doses given during the period
of repeated dosing, a hot meal was served. The
first blood sampie of each series was taken
shortly before the drug was administered (0 hr) .
Single intramuscular dose. A single 50 mg
440 Dahl and Strandjord Clinical Pharmacology
and Therapeutics

PATIENT 2
200
Single dos es Multiple oral dosing. 100mg x 2
50 mg i.m. ..---.. CPZ - CPZ
:::- 100 100 mg orally _ CPZ 0-0 CPZSO
E 0 - 0 CPZSO

cn
c: 50
c:
0
"@
cCII o
o
u
c:
0
u
<lJ
E 5
111
!!l
Il.
Day Day Day 33
2 8 14
15 I I I I -1- -L- I !! I!!!!! I
o 6 12 24 12 12 0 6 12 24 36 48
Time after dose (hr)

Fig. 2. Results in Patient 2 (see legend, Fig. 1).

PATIENT 3
200
Single doses Multiple oral dosing. 100mg x 2
50 mg i.m. ..---.. CPZ _CPZ
:::- 100 1. 100 mg orally ...... CPZ Cl--<) CPZSO
E i~~ 0 - 0 CPZSO

cn
c:
c:
0

'@ - .
c
CII
u
c:
...
0 10

.~
u
<lJ
E 5
111 0
!!l
Il.
Day Day Day 33
2 8 14
15 ! 1 I I I I I I 1 !!! I I I ~ ~ I1IIIII111111 I I I
0 6 12 24 36 12 12 0 6 12 24 36 4B
Time after dose (hr)

Fig. 3. Results in Patient 3 (see legend, Fig. I).

dose was injected intragluteally. The patients
were allowed to sit or walk as usual after the
injection. Blood sampies were collected 0,
0.25,0.5, 1, 1.5,2,3,4,6,8, 12,24, and 36
hr after the injection.
Single oral dose. A single 100 mg oral dose
was given 1 wk after the single intramuscular
dose. Blood sampies were collected after 0, 1,
2, 3,4,5,6,8, 12,24, and 36 hr.
Repeated oral dosing. Oral maintenance
dosing with 100 mg twice daily was started 2
days after the single oral dose_ A blood sampie
was collected shortly before the morning dose
(12 hr after the evening dose) on days 8 and 14_
The maintenance dosing was stopped on day
33, when only the morning dose was given.
Blood sampies were collected at 0, 1,2,3,4,5,
6,8, 12,24,36, and 48 hr after the last dose.
Blood sampling and assay procedure. A 5
to 10 ml sampie of blood was collected from a
cubital vein into heparinized polyethylene
tubes, immediately centrifuged, and the plasma
Vo/ume 2/ Chlorpromazine kinetics after single and chronic dosage 441
Number 4

PATIENT 4

Single doses Multiple oral dosing. IDDmg x 2

50 mg Im A---A CPZ _CpZ
100 mg orally ........ CPZ cpzsa
cpzsa 0-0
0-0

o
c o
CIJ
u
C
o
u
<ll
E
11\
<ll
!L
Day Day Day 33
2 8 14
15 [ " . " [ " , , . 1 1 1 -L -L- IU'~'L"U.~I~"u'~'L.J~______~1______~LI______~I

o 6 12 24 36 12 12 0 6 12 24 36 48
Time after dose (hr)

Fig. 4. Results in Patient 4 (see legend, Fig. 1).

PATIENT 5
200
Single doses Multiple oral dosing. IOD mg x 2
50 mg i.m. "---A CPZ - CPZ
::- 100 IOD mg orally ........ CPZ <>-<> cpzsa
E <>-<> cpzsa
Ol
c

0
c
o
~ ----4-

c
C1J
---&

u
c 10
0 o
u
<ll
E 5
11\
<ll
CL
Day Day
2 8 14
15 1"".1".,,1 I 1 -L-L-
o 6 12 24 36 12 12 12 24 36 48
Time after dose (hr)

Fig. 5. Results in Patient 5 (see legend, Fig. I).

frozen in two aliquots. An indwelling cannula
was used for the 9 or 11 sampIes taken during
one day, and a Wassermann ne edle was used
for the other sampIes . Plasma sampies were
stored at - 24 0 C until analyzed by a gas-
chromatographie method 6 based on flame ioni-
sation deteetion. Two aliquots from the same
plasma sampie were analyzed on different days,
with two injeetions into the gas ehromatograph
for each plasma aliquot.
Pharmacokinetic calculations. Pharmaeo-
kinetie eonstants were ealculated for eaeh sub-
jeet by previously derived equations,5 assuming
first-order kinetics for the elimination of ehlor-
promazine.
Total area under the single dose eurves:
The area under the experimental part of the
eurve (A O- T ) was ealculated by the trapezoidal
rule.
442 Dahl and Strandjord Clinical Pharmacology
and Therapeutics

PATIENT 6
200
Single doses Multiple oral dosing, 100 mg x 2
50 mg i.m. "---6 CPZ ..-. CPZ
::- 100 100 mg orally ..-. CPZ C>--O cpzsa
E
Ol
~
. .....
,~ \
<>---<> C pzsa

c 50
"&,

c
o
" 20
C
41
u
C
---A

o
u
ro
E 5
111
.!E o o
Cl.
Day Day
2 8 14
1.5 OLw...!'-'--'-!6~...J...J..J':----::-'-------=, -L---L 1,",,1"",1
12 12 0 6 12 24 36 48
Time after dose (hr)

Fig. 6. Results in Patient 6 (see legend, Fig. I).

Total clearanee, relative to F, for single and Results

multiple doses: As already noted, one of the nine patients
D relapsed and had to be withdrawn after the first
CI/F = (2)
A o- oo part of the study, the intramuseular dose. The
D others were in a stable mental eondition
C!/F = (3) throughout the drug-free period and the rest of
A~"-:2
the study. Plasma eoneentrations of ehlor-
Apparent volume of distribution, relative to promazine and ehlorpromazine sulfoxide after
F, for single and multiple doses: single and multiple doses are shown in Figs. I
D t. to 8. The areas under the eurves are presented in
V/F = ' (4)
A o- oo In 2 Table I, together with the age and body weight
o . t. of the patients.
V /F = (5) Single intramuscular dose. Highest plasma
A~"12 . In 2
eoneentrations of ehlorpromazine was observed
Biologie availability of single oral doses, 15 or 30 min after the intramuseular injeetion in
relative to single intramuseular doses: all but Patients 2 and 7, who did not reaeh the
maximum until 4 hr after the injeetion. In Pa-
F po (Ao-oo/D)po
(6) tients 1, 2, 7, and 8, the ehlorpromazine plasma
Firn (Ao-oo/D)im
level was relatively stable for 24, 12, 36, and
Estimates for the biologie t! for chlor- 12 hr, respeetively, after the injeetion. Chlor-
promazine and the standard deviation of the es- promazine sulfoxide was not traeed in any
timate were ealculated for eaeh subjeet by linear plasma sampies from the nine subjeets after the
regression analysis. The t! was detennined intramuseular dose.
from the logarithms of the three eoneentrations Single oral dose. Peak eoneentrations of
measured 12 to 36 hr after the single doses, and ehlorpromazine were usually seen 2 or 3 hr after
from the four eoneentrations measured 12 to 48 administration of single oral doses, and were
hr after the last maintenanee dose. The mean t! followed by a relatively rapid fall-off in the
after the single oral dose and the single in- plasma eoneentration during the next 3 to 6 hr.
tramuseular dose was used in estimating the Chlorpromazine sulfoxide was found in plasma
area under the extrapolated part of the eurves from all patients after the single oral dose, but
(Eq. 1) for eaeh subjeet. always in lower eoneentrations than the parent
Vo/ume 2/ Chlorpromazine kinetics after single and chronic dosage 443
Number 4

PATIENT 7
200
Single doses Multiple oral dosing, 100 mg x 2
50 mg i.m. .---. CPZ - epz
=100 100 mg orally _ epz <>-<> CPZSO
E <>-<> epzso
C1l
C

c
o
iii
'-
C
GI
u
~ - - -A- - - - - -- - - - - - --6

C
o
u
<0 o
o
~ 5
<0
CL
Day Day Day 33
2 8 14
1.5 ,-,I-'-'-'-"-'--'-'-'--'-LL-_ _ _-::-IL-_ _ _-II -L ----L lu'-,-'_L.''u'~I-,-,'U'-'-'_L.'I':--_ _ _~I_ _ _---=-'-::'_ _ _-----,'1
o 6 24 36 12 12 0 6 12 24 36 48
Time after dose (hr)

Fig. 7. Results in Patient 7 (see legend, Fig. I).

PATIENT 8
200
Single doses Multiple oral dosing, 100mg x 2
50 mg I.m .---. epz -CPZ
= 100 100 mg or ally e---e ePZ 0----<> CPZSO
E 0-0 cpzsa
C1l
c 50
c
o ..
~ -.--.----._---
~
c
20 -.
GI
u
~ 10 -...
u

Day Day Day 33

2 8 14
-uu~~~~---~2-L.4-----'36 ~ 1T Owl'~'~'w"~~~'u"~'-'-'1~2-----=-2~~---~3~16~-----t8

Time after dose (hr)

Fig. 8. Results in Patient 8 (see legend, Fig. I).

drug. The area under sulfoxide curves were on than the total areas under the single oral dose
average 18% of the area under the correspond- curves in all subjects. The difference in
ing chlorpromazine curve (Table I). areas under single and multiple oral dose
Repeated oral dosing. Chlorpromazine curves was only negligible in Patient 4,
plasma concentrations measured before the ranged from 14% to 59% in the others,
morning dose were either higher (Patients I, 3, and was on average 37% in all eight pa-
4, and 8) on day 33 than on day 8 of repeated tients. The areas under the sulfoxide curves
dosing, Iower (Patients 2, 5, and 6), or virtually within one dosage interval were on average
unchanged (Patient 7). The areas under the 3 I % of the areas under the chlorpromazine
curves within one dosage interval after 33 days curves. The ratio of the area under the sulfoxide
of maintenance dosing were, however, smaller curve to the area under the chlorpromazine
444 Dahl and Strandjord Clinical Pharmacology
and Therapeutics

Table 11. Biologie half-life (with standard deviation in parentheses), apparent volume of distribution,
and total clearanee for ehlorpromazine
t!
(hr)

Single doses
F po
Firn Mean Multiple Cl/Fim VIF im
Subject (0/0) lntramuscularly Oral value dosing (L/min) (L/kg)

1 69 25.5(12.8) 17.2( 5.3) 21.4 22.1( 1.3) 1.09 22.0

2 49 20.2( 1.3) 20.2 41.9(21.3) 1.00 23.6
3 18 17.2( 1.8) 14.3( 2.1) 15.8 35.8( 7.8) 0.53 13.1
4 39 32.3(29.2) 27.7( 7.3) 30.0 26.6( 6.2) 0.44 14.3
5 25 43.9( 2.4) 24.2( 2.4) 34.1 28.2( 1.2) 0.43 17.0
6 10 18.2( 4.8) 1O.9( 1.0) 14.6 27.2( 1.6) 0.65 9.9
7 25 78.6(43.7) 15.9( 3.9) 47.3 26.1( 4.5) 0.50 35.3
8 21 14.2( 1.8) 103.0(32.1) 58.6 35.0( 9.2) 0.50 30.8
Mean 32 31.3 30.5 30.3 30.4 0.64 20.8

eurve was higher after repeated dosing than
after the single oral dose in all subjeets exeept
Patient 6 (Table I). The differenee in this ratio
between single and multiple oral doses was
signifieant (p < 0.01) by the sign test.
Pharmaeokinetie eonstants. The estimates
of biologie availability of ehlorpromazine after
single oral doses, relative to single intramuseu-
lar doses, ranged from 10% to 69% (Table II).
The apparent volume of distribution and the
total clearanee for ehlorpromazine. relative to
its biologie availability, is also given in Table
H. The smaller areas under the eurves within
one dosage interval after repeated dosing, eom-
pared to the total areas under the single oral
dose eurves, are refleeted in an inerease in
Cl/Fpo and V/Fpo from single to multiple oral
dosing.
Plasma levels and adverse reactions. There
were five eases of fainting, always after single
oral or intramuseular doses: Patient 3 fainted
0.5 hr after the intramuseular dose; Patient 4,
0.5 hr after the .intramuseular dose and I hr after
the single oral dose; Patient 6, 12 hr after the
intramuseular dose; and Patient 7, 3.3 hr after
the single oral dose. As may be seen from Figs.
I to 8, all these eases but one (Patient 6) oe-
eurred when the ehlorpromazine plasma eon-
eentrations were above 100 ng/ml. In only one
ease (Patient 5, I hr after the oral dose), was
there a plasma eoneentration above lOO ng/ml
without eoneomitant fainting after a single
dose. No other adverse reaetions were noted
after the single doses, and no adverse reaetions
were seen du ring the period of repeated dosing.
Discussion
The shape of the plasma level eurves ob-
served after intramuseular injeetion in Patients
1, 2, 7, and 8 indieate that the drug was slowly
absorbed from the site of injeetion, whieh has
already been reported 3 : After intramuseular in-
jeetion of 100 mg of ehlorpromazine the plasma
eoneentrations fluetuated between 55 and 78
ng/ml for 24 hr in one patient; in another patient
the highest plasma eoneentration was measured
6 hr after the injeetion.
Beeause of the apparently slow absorption of
the drug after intramuseular injeetion, distribu-
tion equilibrium may not have been attained
after 12 hr, whieh may explain why the esti-
mates of biologie t! were longer after single
intramuseular than after single oral doses in all
but Patients 2 and 8 (Table 11). The total area
under the eurves after intramuseular injeetion
were therefore only approximately estimated (in
Patient 7, the extrapolated part eomprised 64%
of the area).
Pharmaeokinetie parameters for ehlor-
prornazine, estimated from average plasma
eoneentrations after intravenous injeetion of 25
mg in 13 subjeets,16 show a V of 8.1 L/kg,
whieh is eonsiderably smaller than most of the
values for V/Fim given in Table H. This might
 Vo/ume 2/ Chlorpromazine kinetics after single and chronic dosage 445
Number 4

27%; 2, 34%; 3, 65%; 4, 71%; 5, 72%; 6, 57%;

7, 67%; and 8, 67%. These figures may be
overestimating the influenee of a eontingent
Cl/Fpo V IFpo
(L1min) (L1kg) first-pass effeet on the biologie availability,
sinee the estimates of (Ao-oo)im may have been
smaller than the areas under the eurves after
Single Single
oral Multiple oral Multiple an intravenous injeetion of the same dose.
dose dosing dose dosing Nevertheless, in Patients 3 to 8 the bio-
availabilities ealculated by Eq. 7 were sub-
1.58 2.05 31.8 42.6 stantially higher than the values obtained for
2.06 5.03 48.6 246.6
3.00 3.49 74.6 196.4 Fpo/Fim , whieh indieates that a signifieant part
I. II 1.12 36.5 32.7 of the oral doses was lost either by ineomplete
1.68 4.00 67.0 131.9 absorption or by metabolism prior to or during
6.29 8.97 95.8 254.3 the proeess of absorption.
2.00 4.79 141.0 186.4 The faet that no sulfoxide appeared in plasma
2.42 4.84 149.8 179.0
after single intramuseular doses strongly sug-
2.52 4.29 80.6 158.7 gests that the sulfoxide was formed in the gas-
trointestinal lumen or in the intestinal wall.
Similar observations have been reported for the
indieate that the total area under the eurves after eongener methotrimeprazine,5 whieh gave even
intramuseular doses was underestimated, and higher plasma eoneentrations of the sulfoxide
that the biologie availability by oral administra- than of the parent drug after single oral doses.
tion (F po ) therefore was lower than the values However, if sulfoxidation of ehlorpromazine
obtained for Fpo/Fim (Table II). Our results are took plaee only in the gut, the sulfoxide eould
nevertheless in agreement with previously pub- still be formed after parenteral administra-
lished data,12 whieh show that the extent of ab- tion, during enterohepatie reeireulation of the
sorption of ehlorpromazine from tablets was on drug.8. 25, 28
average about 25% of that from doses given It is a general prineiple in linear pharmaeoki-
intramuseularly. neties that the area under the plasma eoneentra-
The relatively low bioavailability of ehlor- tion eurve within one dosage interval at steady
promazine by oral administration eould be due state will be equal to the total area under the
to ineomplete absorption, metabolism in the eurve after a single dose, provided the amount
gastrointestinallumen or in the gut wall, and to of drug reaehing systemie eireulation from eaeh
a first-pass effeet in the liver. If the reduetion in dose, the apparent volume of distribution, and
the available dose by oral administration were the biologie t! of the drug are unehanged. 29
entirely due to a first-pass effeet in the liver, the The smaller areas under the plasma eoneen-
biologie availability might be estimated by the tration eurves within one dosage interval after
equation: 9 33 days of maintenanee dosing, eompared to
the areas under the single oral dose eurves (Ta-
F = I _ 0 (7) ble I), eould be due either to a deerease in ti' a
(AO-oo)im . Q
deerease in Fpo ' or an inerease in V. It may be
This equation is based on the assumptions that noted that the mean t! values from single in-
(1) in eaeh individual the area under the plasma tramuseular and oral doses were used to ealeu-
eoneentration eurve after an intramuseular dose late the area under the extrapolated part of the
would be equal to the area under the eurve after eurves. The reduetion in the total areas under
an intravenous injeetion of the same dose and the single oral dose eurves was not very great
(2) transfer of the drug to the liver was blood when the half-life values from these eurves
flow rate-limited. Substitution of Q = 1.5 were used instead of the mean values, and it did
Llmin and the values given in Table I for Ao- oo not invalidate the eonclusion that the areas
after the intramuseular dose into Eq. 7 yield the under the eurves after repeated dosing were
following values of F for Patients 1 to 8: 1, signifieantly smaller. Although the estimates of
446 Dahl and Strandjord
t! (Table H) must be considered relatively im-
precise, it may be concluded that the biologic t!
was not shorter after 33 days of oral dosing than
after the single oral dose and that the observed
increase in Cl/Fpo from single to multiple doses
was due to an increase in the ratio V/Fpo , as
shown in Table H.
The most plausible explanation for the rela-
tive decrease in the plasma levels after multiple
dosing seems to be that the biologic availability
of the drug was decreased due to increased me-
tabolism in the gastrointestinal lumen or in the
intestinal wall. This explanation is supported by
the observation that the ratio of area under sulf-
oxide curves to area under chlorpromazine
curves increased from single to multiple doses
for aB subjects except Patient 6 (Table I). The
apparent increase in the extent of metabolism in
the gut could be due to induction of drug
metabolizing enzymes in the gut wall or to
adaption of gastrointestinal microorganisms to
the drug. 23
lt has been demonstrated 17 that the rate-
limiting process in the hepatic elimination of
highly distributed drugs may be the transfer of
the drug from peripheral body compartments to
the liver. Thus, changes in intrinsic hepatic
clearance by enzyme induction will have little
effect on the biologic ~ of such a drug. If the
drug is subject to first-pass metabolism, enzyme
induction in the liver may, however, substan-
tiaBy decrease the plasma levels obtained by
oral dosing, without reducing markedly the
biologic t! of the drug. Thus, the relative de-
crease in the plasma levels of chlorpromazine
from single to multiple oral doses may, at least
in part, have been due to enzyme induction in
the liver. Another possible, although less plaus-
ible, explanation for the increase in Cl/Fpo from
single to multiple oral doses is that the apparent
volume of distribution was increased due to
changes in the binding of the drug to plasma or
tissue proteins .
The results from our study indicate that there
is a correlation between the plasma concentra-
tion of unchanged chlorpromazine and the inci-
dence offainting after single oral or intramuscu-
lar doses. It is, however, a well-known clinical
experience that tolerance to acute side-effects
like drowsiness and fall in blood pressure in-
Clinical Pharmacalagy
and Therapeutics
duced by neuroleptic drugs may develop within
a few days of repeated dosing. This was cor-
roborated in this study by Patients 4 and 7, who
fainted after single oral doses although both had
about the same peak concentrations of chlor-
promazine in plasma on day 33 of repeated dos-
ing (Fig. 1) without adverse reactions. It has
previously been reported 13 that no differences in
the benefit of the treatment or in the occurrence
of side-effects were seen whether daily chlor-
promazine doses of 150 mg or 300 mg were
given as three doses a day or as one evening
dose, although the latter dosage scheme would
be expected to give significantly high er peak
concentrations in plasma after each dose.
Several studies of the relationship between
plasma levels and therapeutic response to
chlorpromazine have been performed. Some
have found no correlation between chlor-
promazine plasma levels and clinical effects, 14
whereas other studies have indicated that low
plasma levels of chlorpromazine 2 19, 22 and the
7-hydroxy metabolite l5 , 20 tend to be associated
with a poor response, and vice versa. Almost all
report large individual variations in chlor-
promazine plasma levels relative to dose, and
no clear-cut correlation between plasma levels
and response to chlorpromazine treatment has
been found. This may be due to individual dif-
ferences in the pattern of metabolism, the dis-
tribution of the drug and its metabolites be-
tween plasma and the central nervous system,
and in the relationship between therapeutic re-
sponse and drug concentration at the site of ac-
tion.
Chlorpromazine-treated rats had chlor-
promazine concentrations in the brain 10 times
as high as in the plasma. 4 , 30 The striatal
homovanillic acid levels correlated to the brain
levels of the drug, but not to the plasma drug
levels after repeated dosing. 30 This reflects the
individual variation in the distribution of chlor-
promazine between plasma and the brain. This
variation is probably in the main due to indi-
vidual differences in the binding of the drug to
plasma proteins and tissue constituents.
Cerebrospinal fluid and plasma concen-
trations of chlorpromazine and its sulfoxide
have been measured in two psychiatric patients,
one who responded weil to chlorpromazine
Vo/ume 2/ Chlorpromazine kinetics after single and chronic dosage
Number 4
treatment and one "poor" responder. 1 Both had
about the same CSF/plasma concentration ratio
of chlorpromazine. The chlorpromazine con-
centrations were, however, considerably lower
in the "good" responder than in the "poor"
responder, who showed remarkably high CSF
concentration of chlorpromazine sulfoxide.
Such observations suggest that the lack of corre-
lation between chlorpromazine plasma levels
and c1inical effects may not be explained solely
by differences in the distribution of the drug
to the central nervous system. Several differ-
ent chlorpromazine metabolites accumulate in
plasma by chronic treatment,24 and it is not yet
c1ear to what degree and how each may contrib-
ute to the effects of the drug.
The authors wish to thank Or. J. Bremer at Gaus-
tad Hospital for his helpfulness and interest in the
study and Or. S. Jacobsen at the Institute of Phar-
macology for valuable discussions on the results and
in the planning of the study. We are also indepted to
the patients who volunteered, and to Miss T.
Morsund, Mrs. S. Ellefsen, and Mrs. E. Rystad for
skillful technical assistance.
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