Pharmacokinetics lecture 3 Contents ...

1. Pharmacokinetics lecture 3Contents ... • Compartments • Bioavailability • Salt factor

2. Compartments T3 Compartment 1 Blood + tissues 1 & 2 Blood T2 T1 Compartment 2 Tissues 3 & 4 T4

3. Compartments • The sum of all those tissues into which a drug distributes at approximately the same rate.

4. Single compartment All tissues penetrated rapidly or not at all. Combine blood and all penetrated tissues (T1 & T2) as a single compartment. Drug assumed to spread ‘instantly’ throughout all of this space. T1 T4 Blood T2 T3

5. Single compartment D V

6. Two compartments Drug penetrates some tissues rapidly and others slowly. Combine blood and rapid tissues (T1 & T2) as first compartment. Drug spreads ‘instantly’ through this compart-ment. Combine slow tissues (T3 & T4) as second compartment. T1 T4 Blood T2 T3

7. Blood flows

8. Two compartments D V2 V1

9. Bioavailability (F) • The fraction of a dose that reaches the systemic circulationin a chemically unaltered form. • Fractional availability = F • Quote as percentage or decimal e.g. 25% or 0.25 • Has no units.

10. Incomplete oral bioavailability 2. Chemical, enzymatic or bacterial attack 4. First pass metabolism in gut wall or liver 3. Failure of absorption & Pgp efflux Liver 1. Failure of disintegration or dissolution

11. Failure of absorption • May be due to: • Binding to other molecules in the gut contents • Too polar to undergo passive diffusion • Efflux due to P-glycoproteins

12. First pass metabolism in the gut wall Intestinal epithelium is rich in drug metabolising enzymes. Main Cyt P450 is CYP3A4 Cytochrome P450 activity in intestinal epithelium relative to liver (%) Duodenum Ileum Colon 50 30 10 2 Jejunum

13. Oral bioavailability

14. Blood drainage from G.I.T. General circulation Mouth Stomach Small intestine Large intestine Liver Rectum General circulation

15. Salt factor (S) The drug administered may not be chemically identical to the drug measured in blood. e.g. Phyllocontin tablets contain 225mg of aminophylline. But, target plasma conc. normally quoted as a theophylline conc. Aminophylline contains approx. 80% theophylline by weight. S = 0.80

16. Salt factor (S) Predict initial plasma concentration of theophylline when 500 mg aminophylline injected i.v. into 70 kg adult. (V = 0.48 L/kg) V = 0.48 L/kg x 70 kg = 33.6 L C = D x S = 500 mg x 0.80 V 33.6 L = 11.9 mg/L

17. Sample calculation A drug is administered as a complex containing 75% (by weight) of the parent drug. The volume of distribution of the drug is 1.8 L/kg. What dose of the complex would need to be administered (i.v) to a 90kg patient in order to achieve an initial plasma concentration of 15µg/L? The dose should be expressed in units of mg.

18. Model answer V = 1.8L/Kg x 90Kg = 162 Litres V = D/C0 D = V x C0 S = 162L x 15µg/L 0.75 = 3,240 µg = 3.24 mg Take account of use of a salt

19. Terms with which you should be familiar ... Compartment Bioavailability First pass metabolism Salt factor

20. What you should beable to do • Describe 1 and 2 compartment systems • Relate differences in blood flow in various tissues to the behaviour of a two compartment system • Define ‘Bioavailability’ • List factors that may limit oral bioavailability • Describe how buccal or rectal administration may increase bioavailability • Incorporate a salt factor into pharmacokinetic calculations