Hepatic clearance Aude - PowerPoint Presentation

1. Hepatic clearanceAude Ferran11August 2021, Padova, Italy

2. BILEMetaboliteLIVERBLOOD1231 : biliary clearance of the xenobiotic2 : metabolic clearance of the xenobiotic3 : biliary clearance of the metaboliteINTESTINEFaecesUrineHepatic clearance2Two ways to eliminate the parent drug

3. Hepatic clearanceBiliary clearanceMechanisms of biliary excretionEntero-hepatic cycleMetabolic clearanceMechanisms Influence of blood flowInfluence of the enzymatic capacitiesInfluence of plasma protein bindingFocus on influence of hepatic clearance on oral bioavailability3

4. hepatic veinhepatic portal vein(deoxygenated blood)hepatic artery(oxygenated blood)4reminder

5. 5Centrifugal circulation of the bileCentripetal circulation of bloodreminder

6. 6Bile between the hepatocytesBile ductreminder

7. bilehepatocyte(Mdr1) P-gpMRP2 (cMOAT) BSEP Bile acidsXenobioticsMdr2 hepatocyte7reminder

8. Biliary excretion8

9. Biliary excretion FEATURESE.g.: glucuronoconjugatesPolar moleculesStrongly ionized (pKa =3)MW > 300Mechanism of secretionPolar moleculesBig molecules (MW > 350)Physiological mechanismsCephalosporins in rats9

10. HighRatDogChickenModerateCat (low capacity of glucuronoconjugation)GoatLowManRhesus MonkeyGuinea pigRabbitHorseBiliary excretionDifferences between speciesRat 80%Dog 60%Man 3%Rhesus 15%Example: Chloramphenicol glucuronide(% of the dose in bile)10

11. 11Biliary excretion Biliary clearanceRatebiliary_excretion = Q biliary x C biliary Ratebiliary_excretion Q biliary x C biliary C plasma C plasma = Clbiliary = Qbiliary x C plasma C biliary

12. 12Biliary excretion Biliary clearanceBiliary flow = 0.5-0.8 mL /min

13. BILEMetaboliteLIVERBLOOD123INTESTINEFaecesUrineBiliary excretion The enterohepatic cycle13

14. 14

15. DrugsExcreted and reabsorbed substancesCefoperazoneUnknownEstradiolConjugates (sulfo, glucurono)Valproic acidGlucuronideSpironolactoneMetaboliteImipramineGlucuronideChloramphenicolGlucuronideDigitoxinConjugates (sulfo, glucurono)Biliary excretion The enterohepatic cycle15

16. Sulindac and its metabolites before and after breakfast. Dobrinska MA. J Clin Pharmacol 29:577, 1989. 16Rebound of concentrations after breakfast Sulindac (circles) Sulfone (squares) Sulfide (triangles).

17. Metabolic clearance17

18. hepatic blood flowHepatic extraction coefficient dependent onenzymatic capacities (metabolism)hepatic blood flowbinding to plasma proteinsHepatic clearanceA model of hepatic clearance18

19. In vitroE: enzymes- Intrinsic clearance (enzymatic capacities)drugEEEHepatic clearanceA model of hepatic clearance19

20. concentrationRate of metabolismVmaxVmax / 2KMV =Vmax . CKM + CMetabolism: Michaelis-Menten kineticsVmax : depends on the amount of enzymesKM : depends on the affinity between the enzyme and the drug20

21. concSpeed Intrinsic Clearance On the graph, it corresponds to the slope of the tangentMetabolism: Michaelis-Menten kinetics21 

22. When C << KM: the kinetic is linear = does not depend on the concentrationThe rate of eliminationis of the first orderThe intrinsic clearance is constant=does not depend on the concentrationMetabolism: Michaelis-Menten kinetics    

23. concVMetabolism: Michaelis-Menten kineticsWhen C << KM: the kinetic is linear

24. In vitroIn vivoFlow rate (Q)°EEEE: enzymes- Intrinsic ClearancedrugEEEE: enzymes- Intrinsic Clearance- Supply of drugplasma proteinshepatic blood flowQ°Hepatic clearanceA model of hepatic clearance24Hepatocyte

25. withHepatic clearanceA model of hepatic clearance25Flow rate (Q)°EnzEnzEnzHepatocyte  

26. fu x Clint << QHHigh hepatic extractionLow hepatic extractionThe hepatic clearance model Classification of drugs26   fu x Clint>> QH 

27. Low EH(<0.3) AntipyrinDiazepamPhenylbutazonTheophyllineTolbutamideWarfarinHigh EH(>0.7)LidocainMeperidinPropoxyphenPropranololVerapamilIntermediate EHQuinidinThe hepatic clearance model Classification of drugs27

28. The hepatic clearance modelInfluence of biologic determinantsHepatic blood flowEnzymatic capacitiesBinding to plasma proteins28

29. EHQHEHClHEH > 0.7EH < 0.3The hepatic clearance modelInfluence of hepatic blood flow29    

30. Rowland M, Tozer TN. Clinical Pharmacokinetics: Concepts and Applications, 3rd edition, 1995, p. 162The hepatic clearance modelInfluence of hepatic blood flow30(EH>0.7)(EH<0.3)

31. ClintEHClHThe hepatic clearance modelInfluence of enzymatic capacities31EHEH > 0.7EH < 0.3    

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33. Note : interaction between warfarin and rifampicinWarfarin (EH<0.3) kinetics before (white dots) and after (black dots) treatment with rifampicin. The hepatic clearance model33Influence of enzymatic capacitiesO'Reilly RA. Interaction of sodium warfarin and rifampin.Ann Intern Med 81:337-40, 1974.

34. fuEHClHThe hepatic clearance modelInfluence of binding to plasma proteins34EHEH > 0.7EH < 0.3    

35. Hepatic clearance and oral bioavailability35

36. SmallintestinesIntestinalepitheliumPortal veinGeneral circulationintestinalhepaticfaecesOral bioavailability METABOLISMABSORPTION36liver

37. Oral bioavailability F% = fabs x Ffirst-passForale = fabs x Fintestinal x FH Forale,max = 1x1xFH Forale,max = 1 - EH 37 Forale,max = what the liver will « let pass »if all the dug is absorbed through intestines and if there is no intestinal metabolism

38. fu x Clint << QHHigh hepatic extractionLow hepatic extractionHigh bioavailability insensitive to variations in QH, fu, Clintfu . Clint >> QHLow bioavailability sensitive to variations in QH, fu, ClintOral bioavailability 38  

39. Use of hepatic clearanceAnticipation of the consequences of enzymatic induction or inhibitionPrediction of oral bioavailabilityPrediction of interindividual variability in internal drug exposureVariability of the oral routeDrug interactions39