PARAMETER FARMAKOKINETIK

Pharmacokinetics
Pharmacokinetics is the study of kinetics of absorption, distribution, metabolism and excretion (ADME) of drugs and their corresponding pharmacologic, therapeutic, or toxic responses in man and animals (American Pharmaceutical Association, 1972).

Applications of pharmacokinetics studies include:

Bioavailability measurements Effects of physiological and pathological conditions on drug disposition and absorption Dosage adjustment of drugs in disease states, if and when necessary Correlation of pharmacological responses with administered doses Evaluation of drug interactions Clinical prediction: using pharmacokinetic parameters to individualize the drug dosing regimen and thus provide the most effective drug therapy.

Biopharmaceutics
Biopharmaceutics is the study of the factors influencing the bioavailability of a drug in man and animals and the use of this information to optimize pharmacological and therapeutic activity of drug products (American Pharmaceutical Association, 1972).

These factors include :

Chemical nature of a drug (weak acid or weak base) Inert excipients used in the formulation of a dosage form (e.g. diluents, binding agents, disintegrating agents, coloring agents, etc.) Method of manufacture (dry granulation and/or wet granulation) Physicochemical properties of drugs (pKa, particle size and size distribution, partition coefficient, polymorphism, etc.).

Paramater Pharmacokinetics :
AUC Ka Tmax Cmax Ke t1/2 Vd Onset of action Duration of action Termination of action Therapeutic range

Sites of drug administration :

Intravascular routes : intravenous Intra-arterial Extravascular routes

Important features of the intravascular route of drug administration :

There is no absorption phase. There is immediate onset of action. The entire administered dose is available to produce pharmacological effects. This route is used more often in life-threatening situations. Adverse reactions are difficult to reverse or control; accuracy in calculations and administration of drug dose, therefore, are very critical.

Important features of extravascular routes of drug administration : An absorption phase is present. The onset of action is determined by factors such as formulation and type of dosage form, route of administration, physicochemical properties of drugs and other physiological variables. The entire administered dose of a drug may not always reach the general circulation (i.e. incomplete absorption).

Review of ADME processes

Absorption Absorption is defined as the process by which a drug proceeds from the site of administration to the site of measurement (usually blood, plasma or serum). Distribution Distribution is the process of reversible transfer of drug to and from the site of measurement (usually blood or plasma). Any drug that leaves the site of measurement and does not return has undergone elimination. Metabolism Metabolism is the process of a conversion of one chemical species to another chemical species Elimination Elimination is the irreversible loss of drug from the site of measurement (blood, serum, plasma). Elimination of drugs occur by one or both of metabolism and excretion. Excretion Excretion is defined as the irreversible loss of a drug in a chemically unchanged or unaltered form.

Compartment concept in pharmacokinetics :

Intravenous bolus administration, one-compartment model :

Intravenous bolus administration, twocompartment model :

Extravascular administration, onecompartment model :

Extravascular administration, two-compartment model :

Intravenous bolus administration, onecompartment model :

Suatu antibiotik diberikan kepada seorang wanita 50 kg dengan dosis IV tunggal 20 mg/kg. Sampel darah diambil secara periodik untuk menentukan kadar obat. Data diperoleh sebagai berikut :

10,0 9,00 8,00 7,00 6,00 5,00 4,00 3,00

Cp0 = 5 mg/l

DB0 = 20 mg/kg x 50 kg = 1000 mg

x
x x

Vd

D0 1000 mg B 200 L 0 5 mg / L Cp

2,00

t1/2=(2,3 1,3)jam = 1 jam

x

Waktu Cp (mg/l) (jam) 0,25 4,2 0,50 3,5 1,00 2,5 2,00 1,25 4,00 0,31 6,00 0,08
Hitung volume distribusi, tetapan laju eliminasi, waktu paruh, dan tuliskan pesamaan kurvanya !

Cp (mg/L)

1,00 0,90 0,80 0,70 0,60 0,50 0,40 0,30

1,3

2,3

k = 0,693/t1/2= 0,693/1 jam-1

= 0,693 jam-1

Cp = 5e-0,693t

0,20

0,10 0,09 0,08 0,07 0,06 0,05

0,04
0,03 0,02

t (jam)
0,01 0 1 2 3 4 5 6 7

Intravenous bolus administration, twocompartment model :

Suatu obat diberikan dengan injeksi IV cepat kepada seorang pria dewasa 70 kg. Cuplikan darah diambil selama 7 jam dan ditentukan kadarnya untuk senyawa obat utuh. Hitung harga intersep A dan B, slope a, b, K, K12, K21 Waktu (jam) 0,00 0,25 0,50 0,75 1,00 1,50 2,00 2,5 3,0 4,0 5,0 6,0 7,0 Cp (g/ml) 70,0 53,8 43,3 35,0 29,1 21,2 17,0 14,3 12,6 10,5 9,0 8,0 7,0

Extravascular administration
Konsentrasi obat dalam plasma pada seorang penderita yang menerima dosis oral tunggal suatu obat (10 mg/kg) didapatkan sebagai berikut. Dengan anggapan bahwa obat 80% terabsorpsi tentukan Ka, t1/2 eliminasi, tmaks, dan Vd

Waktu (jam)
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Konsentrasi (g/ml)
0 23,7 35,4 39,6 39,6 37,2 33,7 29,7 25,8 22,1 18,7 15,8 13,2 11,0 9,14

Extravascular administration
Tentukan : a. t1/2 absorpsi dan eliminasi b. tetapan laju absorpsi dan eliminasi c. Vd d. Cp max e. T max Jika diketahui dosis obat yang diberikan adalah 250 mg dan obat dianggap terabsorpsi seluruhnya. Waktu (menit) Konsentrasi (g/ml)

0 20 40 60 80 100 120 140

0 31 68 101 68 61 36 19