Pharmacokinetics One- compartment Open Model Lec:2

Transcription

1 22 Pharmacokinetics One- compartment Open Model Lec:2 Ali Y Ali BSc Pharmacy MSc Industrial Pharmaceutical Sciences Dept. of Pharmaceutics School of Pharmacy University of Sulaimani 1

2 Outline Introduction Drug disposition Volume of distribution Elimination rate constant Equations of one compartment models Significance of volume of distribution Clearance Ways of expression of Elimination Examples 2

3 Compartment models For understanding the drug disposition in the body, pharmacokinetic (PK) models are used. The model must account for: 1. Route of administration 2. Kinetic behaviour of the drug in the body 3

4 Mammillary Models 1. One- compartment open model Ka: absorption rate constant K: elimination rate constant 2. Multi- compartment open model (Shargel, Wu- Pong et al. 2007) 4

5 One- compartment Open Model Simplest model to describe drug distribution and elimination of drugs. This model assumes that the drug can enter or leave the body open the body (tank) acts like a single, uniform compartment. 5

6 Distribution Drug Disposition In the body such that the drug is injected all at once into a box (compartment) and that the drug distributes instantaneously and homogenously. Drug elimination occurs from the compartment immediately after injection (Shargel, Wu- Pong et al. 2007) 6

7 Route of Administration Simplest in terms of Use? Simplest from PK perspectives? Oral IV Bolus VS 7

8 IV bolus The entire dose of drug enters the bloodstream The drug absorption process is considered to be instantaneous. The drug distributes via the circulatory system to potentially all the tissues in the body. 8

9 Drug Uptake Uptake of drugs by various tissue organs will occur at varying rates, depending on Physiological factors :the blood flow to the tissue Drug factors : a) the lipophilicity of the drug b) the molecular weight of the drug c) the binding affinity of the drug for the tissue mass. 9

10 Elimination Most drugs are eliminated from the body either through 1. Kidney and/or 2. Metabolized in the liver Because of rapid drug equilibration between the blood and tissue, drug elimination occurs as if the dose is all dissolved in a tank of uniform fluid (a single compartment) from which the drug is eliminated. 10

11 Volume of Distribution The volume in which the drug is distributed is termed the apparent volume of distribution, V D. The V D is determined from the preinjected amount of the dose in the syringe and the plasma drug concentration resulting immediately after the dose is injected 11

12 Volume of distribution (V D ) Apparent V D The volume that must be considered in estimating the amount of drug in the body from concentration of the drug found in the sampling compartment. No true physiologic meaning. 12

13 Volume of Distribution & Elimination Rate constant The apparent volume of distribution is a parameter of the one- compartment model It governs the plasma concentration of the drug after a given dose. Elimination rate constant, k, governs the rate at which the drug concentration in the body declines over time 13

14 Tissue drug concentration The one- compartment open model does not predict actual drug levels in the tissues. The model assumes that changes in the plasma levels of a drug will result in proportional changes in tissue drug levels The drug in the body, D B, cannot be measured directly, accessible body fluids (such as blood) can be sampled to determine drug concentrations 14

15 Elimination rate constant (k ) rate of elimination for most drugs from a tissue or from the body is a first- order process the rate of elimination is dependent on the amount or concentration of drug present. Elimination rate constant, k, unit is time 1 (e.g., hr 1 or 1/hr). 15

16 Elimination rate constant (k ) The elimination rate constant represents the sum of each of these processes: k = km + ke k m = first- order rate process of metabolism k e = first- order rate process of excretion There may be several routes of elimination of drug by metabolism or excretion Each one of these processes has its own first- order rate constant 16

17 Elimination rate constant (k ) Total elimination of the parent drug from this compartment is effected by metabolism (biotransformation) and/or excretion. 17

18 Equations First- order kinetics D B = drug in the body at time t D 0 = drug in the body at t = 0. log D B is plotted against t for this equation, a straight line is obtained. 18

19 The amount of the drug in the body is measured from blood samples V D relates the Concentration (C p ) of the drug measured and the amount of the drug given D B 19

20 Example 1 g of a drug is dissolved in an unknown volume of water. Upon assay, the concentration of this solution is 1 mg/ml. What is the original volume of this solution? 1 g = 1000 mg: Therefore, the original volume was 1000 ml or 1 L. 20

21 Cont. If, in the above example, the volume of the solution is known to be 1 L, and the concentration of the solution is 1 mg/ml, then, to calculate the total amount of drug present? Therefore, the total amount of drug in the solution is 1000 mg, or 1 g. 21

22 Volume of Distribution apparent volume of distribution smaller than, or equal to, the body mass. some drugs, it may be several times the body mass. apparent V D is dependent on C p0. 22

23 Significance of Volume of Distribution apparent V D is a useful parameter in considering the relative amounts of drug in the vascular and in the extravascular tissues. 23

24 Significance of Volume of Distribution Large apparent V D : drugs are more concentrated in extravascular tissues and less concentrated intravascularly. Small apparent V D : drug is highly bound to plasma proteins or remains in the vascular region, then C p0 will be higher 24

25 V D of some drugs 25

26 V D & body weight The apparent V D can be expressed as a simple volume or in terms of percent of body weight. In expressing the apparent V D in terms of percent body weight, 1- L = 1 kg. For example, if the V D is 3500 ml for a subject weighing 70 kg, the V D expressed as percent of body weight is 26

27 V D & body weight Values bigger than 100 % indicates that the drug may be concentrated in a certain tissue. 27

28 Clearance Drug clearance Systemic clearance Total body clearance (Cl T ) Measure of elimination of a drug Regardless of the mechanism or the process It considers the body as a drug eliminating system

29 Clearance in the One- compartment Body: System of organs model Highly perfused (blood, plasma) Elimination is continuous process (metabolism and excretion) Elimination is complex The concept of clearance is used to quantify elimination

30 Ways of Expression of Elimination A. Amount(weight) / time B. Volume/ time (Clearance) C. Fraction/ time

31 A. Elimination as Amount /time Units : mg/ min, mg/hr Simple, absolute Convenient for zero- order elimination process As drug is eliminated in constant amounts Not useful for first- order elimination process

32 B. Elimination as Volume/time Clearance: concept of expression of the rate of removal in terms of volume of drug solution/ time. Drug concentration in the body decline by first- order kinetics Mass of the drug removed over time is not constant Plasma volume is relatively constant under normal conditions

33 Constant volume of fluid is filtered by the kidneys 120 ml/min Rate of elimination is proportional to the drug concentration based on first order kinetics

34 Clearance Volume removal of drug It is constant regardless of concentration Cl = K V D

35 C. Elimination expressed as Fraction Eliminated /time Applicable regardless of using amount or volume Most flexible and convenient Expresses elimination as fractions One tenth of the drug mount One tenth of the volume of drug solution

36 Elimination expressed as Fraction Eliminated /time PK incorporates this concept of the first- order equation that considers elimination from one compartment model

37 Half life (t 1/2 ) Period of time required for amount (D) or concentration (Cp)of a drug to decrease by one half. Constant t "/$ = &.()*, 37

38 Example 1 A 70- kg volunteer is given an intravenous dose of an antibiotic, and serum drug concentrations were determined at 2 hours and 5 hours after administration. The drug concentrations were 1.2 and 0.3 µg/ml, respectively. What is the biologic half- life for this drug, assuming first- order elimination kinetics?

39 Example 2 A new drug was given in a single intravenous dose of 200 mg to an 80- kg adult male patient. After 6 hours, the plasma drug concentration of drug was 1.5 mg/100 ml of plasma. Assuming that the apparent V D is 10% of body weight, compute the total amount of drug in the body fluids after 6 hours. What is the half- life of this drug?

40 Example 3 A single IV bolus injection containing 500 mg of cefamandole nafate (Mandol, Lilly) is given to an adult female patient (63 years, 55 kg) for a septicemic infection. The apparent volume of distribution is 0.1 L/kg and the elimination half- life is 0.75 hour. Assuming the drug is eliminated by first- order kinetics and may be described by a one- compartment model, calculate the following:

41 Cont. a. The C p 0 b. The amount of drug in the body 4 hours after the dose is given c. The time for the drug to decline to 0.5 µg/ml, the minimum inhibitory concentration for streptococci

42 Parameters used in PK 42

43 Any Questions 43

44 Further Readings Shargel, L., S. Wu- Pong and A. B. Yu (2007). Applied biopharmaceutics & pharmacokinetics, McGraw- Hill. Aulton's Pharmaceutics: The Design andmanufacture of Medicines, M.E.Aulton, Churchill Livingstone,

45 Thank You 45