1. Intrinsic Clearance Arthur G. Roberts

2. Hydrophobic vs. Hydrophilic more bound to plasma proteins more distributed throughout body more metabolized

3. K m = rate constant for formation of metabolite Y = rate constant for the elimination of drug X = not the Michaelis-Menten constant K r = rate constant for the excretion of drug Y Hypothetical Example KrKr

5. fastslow * Slowest Step Determines the Rate KrKr

6. slow rel. fast * Slowest Step Determines the Rate KrKr

7. Concentration dose (mg) [Drug] = Volume Distribution (L)

8. “Steady State” Concentration [Drug] steady state = drug infusion rate (mg/hr) total body clearance (L/hr) [Drug] steady state = drug going in (mg/hr) drug going out (L/hr)

9. Extraction Ratio (Efficiency) Extraction Ratio = ([Drug] in -[Drug] out )/[Drug] in Organ Clearance = Blood Flow (L/hr) (Q)* Extraction Ratio (E) Liver artery [Drug] in [Drug] out vein Elimination

10. Effect on Clearance

11. Hepatic Clearance Major site of metabolism Pass through liver before systematic (First Pass) – receives most blood supply from GI.

12. 12 HEART GUT LIVER BODY Portal Vein Artery

13. 13 HEART GUT LIVER BODY Portal Vein Artery

14. 14 HEART GUT LIVER BODY Portal Vein Artery

15. 15 HEART GUT LIVER BODY Portal Vein Artery

16. 16 HEART GUT LIVER BODY Portal Vein Artery

17. 17 HEART GUT LIVER BODY Portal Vein Hepatic Artery

18. Michaelis-Menten and Intrinsic Clearance artery [Drug] in [Drug] out vein Elimination of P Liver E+S  ES  P fast slow fast S=Drug P=Metabolite

19. Michaelis-Menten vs. Intrinsic Clearance v = V max [S] K m + [S] v = velocity = ([S]*Volume Metabolized (L))/hour Cl int = v/[S] (Volume Metabolized (L))/hour [S]=[Drug] Cl int = = v [S] V max K m + [S] v

20. Extraction Ratio and Intrinsic Clearance Extraction Ratio = Cl int (L/hr) Blood Flow (L/hr) + Cl int (L/hr) Can the intrinsic clearance be higher than the blood flow? If an enzyme that is involved in metabolizing a drug is induced, what is the effect on Cl int ?

21. Intrinsic (Cl int ) and Hepatic Clearance (Cl h ) Cl h = Hepatic Blood Flow (Q h ) * Extraction Ratio (E) Extraction Ratio (E) = Cl int (L/hr) Blood Flow (L/hr) (Q h ) + Cl int (L/hr) Cl h = Q h * Cl int (L/hr) Q h (L/hr) + Cl int (L/hr)

22. Modeling Hepatic Clearance Output Conc. after going through the liver Conc. along Liver

23. Well Stirred Model Cl h = Q h * Cl int (L/hr) Q h (L/hr) + Cl int (L/hr) Assuming the Drug is 100% Unbound and Free to get Metabolized Assuming that there is a fraction of unbound drug (F unbound ). Cl h = Q h * F unbound * Cl int (L/hr) Q h (L/hr) + F unbound * Cl int (L/hr)

24. E = Cl int (L/hr) Q h (L/hr) + Cl int (L/hr) Cl int =Cl i = intrinsic clearance

25. End of Intrinsic Clearance