1. Hawler Medical University
Pharmacokinetics 4th stage Distribution of the drug in the body (Volume of Distribution) Lec. -1-
By:
Dr. Raad A. Kaskoos
Ph. D. Pharmaceutics
Pharmaceutics Dept.
Hawler Medical University
College of Pharmacy

2. Volume of distribution (Vd)
Is a useful parameter that relates plasma drug concentration to the amount of drug in the body
In multiple compartment kinetics there are several volume of distribution

3. Volume of distribution (Vd), cont.
There are several volume of distribution that may be considered for a drug that assumes a two compartment open model such as volume of the central compartment and the volume of the peripheral or tissue compartment.

4. Apparent volume of the central compartment Vc
It is useful for describing changes in drug concentration
In the determination of drug clearance
The magnitude of Vc gives an indication of the distribution of the drug in the body water

5. Apparent volume of the central compartment Vc , cont.
As in the case of one compartment model, Vc may be determined from the dose and the instantaneous plasma drug concentration Cc
Vc can be calculated by the following equation:
Vc = X0 / Cc

6. Apparent volume of the central compartment Vc , cont.
Vc = X0 / Cc Where: Vc = Volume of distribution of the central compartment X0 = Amount of the drug at zero time Cc = Plasma drug concentration

7. Apparent volume of distribution at steady state
At steady state conditions the rate of drug entry into the tissue compartment from the central compartment is equal to the rate of drug exit from the tissue compartment into the central compartment
The rate of drug transfer are described by the following eqation:
Xp K21 = Xc K12

8. Apparent volume of distribution at steady state, cont.
Xp K21 = Xc K12 Xp = Xc K12 / K21 And the amount of drug in the central compartment Xc is equal to Vc Cc , then by substitution in the above equation: Xp = K12 Vc Cc / K21

9. Apparent volume of distribution at steady state, cont.
The total amount of drug in the body at steady state is equal to the sum of the amount of drug in the tissue compartment Xp , and the amount of drug in the central compartment Xc
Therefore, at steady state, the apparent volume of drug (Vd)ss may be calculated by dividing the total amount of drug in the body by the concentration of drug in the central compartment at steady state:
(Vd)ss = Xc + Xp / Cc

10. Extrapolated volume of distribution (Vd)exp
can be calculated by the following equation: (Vd)exp = X0 B Where: (Vd)exp = Extrapolated volume of distribution X0 = Amount of the drug B = is the intercept

11. Volume of distribution by area (Vd)
It is also known as (Vd)ß
It is obtained through calculation similar to those used to find Vc , except that the rate constant ß is used instead of elimination rate constant Ke
(Vd)area = (Vd)ß = X0 / ß (AUC)0

12. Significance of the volume of distribution
Volume of distribution is affected by changes in the overall elimination rate and by the change in the total body clearance of the drug
After the drug is distributed, the total amount of drug in the body during the elimination of ß phase is calculated by using (Vd) area

13. Significance of the volume of distribution, cont.
Whereas (Vd)ss is not affected by changes in drug elimination, (Vd)ss reflects the true distributional volume changes due to renal function
Vc represent the apparent volume of the central compartment and is useful in the calculation of drug clearance

14. Significance of the volume of distribution, cont.
The magnitude of the various apparent volumes of distribution have the following relationship to each other:
(Vd)exp > (Vd)area > Vc
For drugs that follow two compartment model kinetics, changes in disease states may not result in different pharmacokinetic parameters

15. Significance of the volume of distribution, cont.
Conversely, changes in pharmacokinetc parameters should not be attributed to physiologic changes without careful consideration of method of curve fitting and intersubject difference
The terms K12 and K21 often fluctuate due to minor fitting and experimental difference and may affect calculation of other parameters

16. Drugs in the tissue/peripheral compartment
The apparent volume of the tissue compartment Vp is a conceptual volume only and does not represent true anatomic volumes
The Vp may be calculated from the knowledge of the transfer rate and Vc as follows:
Vp = Vc K12 / K21
The calculation of the amount of drug in the tissue compartment does no entail the use of Vp

17. Drugs in the tissue/peripheral compartment, cont.
Calculation of the drug concentration in the tissue compartment is useful, since the pharmacologic activity may correlate better with the tissue drug level time curve
The amount of drug in the tissue compartment is also related to the amount of drug in the central compartment and the transfer constants

18. Elimination rate constant
In the two compartment model (I.V administration) the elimination rate constant Ke represents the elimination of drug from the central compartment
Whereas ß represents the elimination of drug from the entire body after the diffusable drug has established an equilibrium
Therefore, ß is useful in calculating t1/2 and multiple dosage regimens

19. Two compartment open model intravenous infusion

20. Two compartment open model intravenous infusion, cont.

21. Two compartment open model-extravascular administration

22. Two compartment open model-extravascular administration, cont.

23. Three compartment open model
It is an extension of the two compartment model with an individual deep tissue compartment
The drug is distributed most rapidly to a highly perfused central compartment, less rapidly to the second or tissue compartment and very slowly to the third or deep tissue compartment

24. Three compartment open model, cont.

25. Three compartment open model, cont.

26. Determination of compartment models
Models based on compartmental analysis use the fewest number of compartments necessary to adequately describe the experimental data
Once an empirical equation is derived from the experimental observations, it becomes necessary to examine how well the theoretical values calculated from the derived equation fit the experimental data

27. Determination of compartment models, cont.
Depending on the sampling intervals, it is also possible to miss a compartment
Samples may be taken too late after administration of the dose to observe a possible distributive phase
For example the following data plotted could easily mistaken for those of one compartment model as follows:

28. Determination of compartment models, cont.

29. Determination of compartment models, cont.
In describing compartments each new compartment requires an additional first-order plot
Compartment models having more than three compartments are rarely of pharmacologic significance
In certain cases it is possible to lump a few compartments together to get a smaller number of compartments which together will describe the data adequately

30. Determination of compartment models, cont.
An adequate description of several tissue compartments may be difficult
Addition of a compartment to the model seems necessary
It is important to realise that the drug may be retained or slowly concentrated in a deep tissue compartment

31. Any Questions?

32. The End… Thank you….