Variability of Hepatic Drug Metabolism & Dosage Adjustment

1. Variability of Hepatic Drug Metabolism & Dosage Adjustment

2. Objectives • Discuss hepatic disease and other factors which impact hepatic drug metabolism. • Review calculations of Hepatic extraction and clearance. • Understand the impact of hepatic first pass extraction on oral bioavailability. • Based on the extraction ratio, estimate whether the clearance of a drug will be mainly dependent on liver blood flow rate or intrinsic enzyme activity. • Calculate hepatic clearance, extraction, half-life and dosage requirements based on changes in blood flow and intrinsic metabolic activity in patients.

3. HEPATIC CLEARANCE • Important drug clearance route. Most lipid-soluble drugs are metabolized by one or more enzymes within the liver. • As liver is major metabolic organ, generally consider hepatic clearance as metabolism.However drugs and their metabolites can also be secreted from hepatocytes into bile. Biliary Secretion • Hepatic disorders caused by multitude of diseases. • - Has impact on a number of metabolic enzyme systems and physiological factors within the liver.

4. 2 Major types of Liver Disease Cirrhosis- Hepatoctyes replaced by non-functional connective tissue. - Permanent loss of functional hepatocytes. - Portal vein hypertension and shunting of blood flow around liver. -  Liver blood flow -  Production of plasma proteins Hepatitis- Inflammation of liver causing  function or cell death of hepatocytes. Acute- Mild/ Transient changes in hepatic function Chronic - Often irreversible hepatocyte damage - Can progress to cirrhosis. HEPATIC DISEASE

5. Effect on Metabolism • 1) Enzyme Activity/Capacity • - Effects on drug metabolism may be different depending on enzyme system. • Cirrhosis: • Generally see  Drug metabolism • require dosage adjustment. • Acute Viral Hepatitis: • Some drugs changed • approx 50% of drugs affected

6. 2) Hepatic Blood Flow: •  Q in chronic liver disease (cirrhosis, alcholism, hepatitis). • portal blood shunted (bypass liver) • PK EFFECTS: • Alterations in Hepatic Clearance (CLH) and F (Liver Bioavailability ) • DOSES OF METABOLIZED DRUGS OFTEN NEED TO BE REDUCED

7. Likewise enzyme capacity/ affinity and/or liver blood flow also affected by : • Genetic polymorphisms • Exposure to drugs/ environmental • Age • Physiological Factors • Activity, cardiac output • Other Diseases • Inflammatory disease • Renal disease • All important sources of variability in hepatic clearance.

8. Hepatic Clearance LIVER Blood OUT Blood IN 25% Hepatic Artery 75% Portal Vein Hepatic Vein Bile • Remember: • Physiological definition of Hepatic Clearance is dependent on Blood flow (Q) to the liver and Efficiency of the liver to clear the drug from blood. • CL H = Q (ER)

9. CLH : Hepatic Clearance • Q: Flow rate through liver • ER: Hepatic Extraction Ratio • (0-1) • represents the proportion of drug entering liver that is metabolized or excreted upon EACH pass through the liver. • ER= CLH/Q

10. Plasma vs Blood Q = Liver Flow Blood:Q =1.5 L/min Plasma Q = 825 ml/min Use: Plasma flow with plasma clearance & Blood flow with blood clearance Q plasma = (1- HCT) Q blood HCT = hematocrit Thefraction of blood volume which is taken up by erythorcytes. Average HCT = 0.45

11. Drug can be removed by liver in two manners: • Removal of drug from the systemic circulation • Hepatic Clearance- (CLH) is a component of total body clearance. • Drug dissolved in blood/plasma is removed during each pass through liver. • 2) Pre-systemic removal of drug (1st pass) • Drug is directly absorbed into portal vein and exposed to liver prior to entry into systemic circulation. • Removal of drug upon the 1st pass through liver decreases oral bioavailability. • Hepatic 1st pass Extraction is a component of oral bioavailability.

12. Therefore, Liver extraction efficiency impacts both systemic hepatic clearance (hepatic clearance) and oral bioavailability (1st pass effect) of drugs. • Need to consider systemic availability for orally administered drugs. • Fraction remaining after 1st pass thru liver (fer ): • fer = 1 - ER • fer Liver bioavailability, • liver first pass availability. But also need to consider absorption!

13. Oral bioavailability (F) involves a combination of processes: - dissolution in gut (fdis) - absorption (fabs) - liver first pass (fer) F = fdis x fabs x fer If entire dose is absorbed : fdis = 1 , fabs = 1 so F would be equal tofer Remember: F * Dosepo = Doseiv Bioavailability (F)

14. Problem • A new drug Zee® is completely eliminated through hepatic metabolism to inactive metabolites. • After a 100 mg IV dose to healthy patients, plasma samples were collected, a total body clearance (CLT) of 400 mL/min • was calculated.

15. Q1. What is the predicted hepatic ER of Zee® ? • ER = CLH / QH • -

16. Q2. Assuming complete intestinal absorption, what is the equivalent oral dose of Zee® ? • fer = 1-ER

17. Q3. If the intestinal absorption of Zee® is incomplete (70%) - what oral dose is required? • F = fdis x fabs x fer

18. Not always so simple….. • Hepatic extraction is dependent on • several factors that can change

19. ER dependent on: 1. Uptake of drug (partitioning) 2. Amt of enzyme 3. Metabolic activity (Vmax, km) 4. Blood flow (Qh) 1, 2 & 3 = Intrinsic clearance (CLint) ER = CLint__ CLint + Qh Calculation of ER based on mechanism Capacity & Affinity

20. Substituting ER with CLH (ER= CLH/Q) to describe in terms of CLH: CLH = Qh * CLint_ CLint + Qh Rearrangement of equation to describe relationship in terms of CL int : CL int = CLH * Qh ( Qh -CLH) Other important equations describing this relationship:

21. CLint – Intrinsic clearance. The inherent ability of the liver to metabolize drugs in the absence of limitations. Ideal situation. Reflects total enzyme activity. • CLH- “actual clearance” – based on intrinsic enzyme activity and limitations (factors which limit access to metabolic enzymes). • These equations allow us to describe CLH and ER based on liver blood flow and enzyme parameters

22. Describing clearance in all possible terms (ie- using the more complex equations, which factor in CLint) allows us to estimate drug clearance when physiologic or disease conditions causes changes in either liver blood flow or intrinsic enzyme activity. • Intrinsic enzyme activity can change: • Genetic polymorphisms • Environmental pollutants • enzyme induction • Drug-drug interactions • enzyme induction/ inhibition. • - Hepatic Disease • Liver Blood flow can change: • Activity ( Q) • Posture • Food ( Q) • Hepatic Disease • Changes in cardiac output

23. Estimating Impact of Changes • Relative impact of changes in Q or enzyme activity (Clint) on the hepatic clearance, bioavailability or half-life of a drug depends on how efficiently the drug is removed/extracted by the liver • Generally ***….. • High: ER > 0.7 • Very efficiently removed from liver. • Low: ER< 0.3 • Low efficiency in extraction • Intermediate ER 0.3 - 0.7 • ****This an arbitrary division of groups – there is no absolute ranking system.

24. Typical drug examples • High ER : • Verapamil, lidocaine, propranolol, nitroglycerin, cocaine, morphine • Intermediate ER: • Aspirin, Quinidine • Nortriptyline • Low ER: • Antipyrine, NSAIDs, Diazepam, • Erythromycin, Phenytoin • Theophylline, Warfarin • * Low ER does not mean it is not metabolized.

25. Impact of variability in Q and enzyme function on • Hepatic Clearance (CLH)

26. Highly Extracted Drugs Clint >>> Qh CLH Qh * CLint_ CLint CLint terms cancel out.  CLH  Qh Hepatic clearance approximates blood flow. Qh is limiting factor Flow dependent/limited. • CLH = Qh * CLint_ • CLint + Qh CLint is approx equal to ( CLint + Qh)

27. CLH = Qh * CLint_ • CLint + Qh • Low Extracted Drugs • (ER<0.3) Qh >> CL int • So (Clint + Q) is approx equal to Q • CLH Qh * CLint_ Qh • CLH  CL int • Hepatic Clearance approximates inherent metabolic activity. • CLint is limiting factor • CAPACITY LIMITED.

28. Effect of Physiological changes on CLH Based on this…should be able to make”quick” initial prediction on drug metabolism & clearance for high and low extracted drugs. No shortcuts for Intermediate Extraction drugs. Relative changes in ER (bioavailability) will be differentially affected by changes in Q or CLint . The relative tendency after moderate changes. For instance if blood flow decreases to 0 …… You should be calling 911, not estimating hepatic clearance. Dramatic changes will affect clearance of all drugs.

29. Dosage Route 1) IV doses -Consider effects on hepatic clearance and t½. 2) Oral doses - Consider effects on 1st pass through liver (fer) , hepatic clearance and t½ - 1st pass is an important parameter for High E drugs. - Since so much drug enters liver on 1st pass, both Qh and CL int are important - If Q too fast: ed access to enzymes

30. Impact of Variability of liver blood flow and enzyme activity on oral bioavailability.

31. fer = 1 - ER = 1- [ CL int/ (CLint+Qh)] fer = __Qh___ CL int + Qh High ER: CL int >> Qh fer Qh / CL int substitute in equation for ER as defined by CLint * fer is dependent on BOTH Qh and CLint

32. Change in Blood Flow:Sample Problem Two drugs (A & B) are completely metabolized in the liver by CYP2D6. The following is known about A & B* * Blood data. Qh = 1.5 L/min DRUG V (L) CLT (L/min) t1/2 (hr) A 30 0.15 2.31 B 30 1.35 0.26 Intestinal absorption is complete for both drugs. Q. Determine expected CLT, t1/2 and F of Drug A & B in congestive heart failure patients which have a 40% in cardiac output - 40%  CO

33. Solution: (CO by 40%)then Q by 40% - Assume CL int is unchanged Calculate original CL int - based on original values of Q & CLH.

34. ii) Determine CLH • use new Q and original CL int

35. iii) Determine t½ using new CLT • (CLT = CLH) • - assume V not changed

36. iv) Calculate ER • - use new CLH and new Q • v) Calculate fer using new ER

37. Summary of Problem Set

38.  LIVER BLOOD FLOW ER = 0.1 ER = 0.9 • CLH ↑ t½ IV  fer • CLH ↑ t½ PO High ER: fer  Qh / CL int

39. Changes in Enzyme Activity. Problem –part B Two drugs (A & B) are completely metabolized in the liver by CYP2D6. The following is known about A & B* * Blood data. Qh = 1.5 L/min DRUG V (L) CLT (L/min) t1/2 (hr) A 30 0.15 2.31 B 30 1.35 0.26 Intestinal absorption is complete for both drugs. Q. Calculate the expected CLT, t1/2 and F of Drug A & B in patients with CYP2D6 polymorphism that is associated with 50 %  in enzyme activity ( 50 %  CLint ).

40. Assume only CLint changes, - no change in Q. Calclulate original CL int . ii) Calculate new CL int . Polymorphism: 50% CL int Solution :

41. iii) Determine CLH • - use new CL int and original Q • CLH = Qh* CLint_ • CLint+ Qh

42. iv) Determine t1/2 using new CLT (CLT = CLH) • - assume V not changed

43. v) Calculate ER using new CLH • - with original Q • vi) Calculate fer

44. Summary of Problem Set

45.  INTRINSIC CLEARANCE ER = 0.1 ER = 0.9 • CLH ↑t½ IV • CLH ↑t½ F PO High ER: fer  Qh / CL int

46. Review graphs depicting general changes in plasma drug concentration time curves with alterations in Q or CLint • - - Page 342 –343 Applied Biopharm & PK 5th Ed.

47. Dosage Adjustment in patients • Still talking about the same two drugs… • The standard daily oral dose required to obtain a therapeutic steady state concentration in normal patients is: Drug A = 25 mg • Drug B = 200 mg • Q. Calculate the oral dose of Drug A and Drug B required in patients with the CYP2D6 polymorphic SNP varients (50% activity).

48. Css = FN *DOSEN= FP *DOSEP • CLTN *τCLTP* τ • Using N subscript to refer to normal and P subscript to refer to patient with polymorphism. • If using same dosing intervals (τ) – terms cancel out • So…. • FN *DOSEN = FP *DOSEP • CLTN CLTP

49. Solution: • Drug A • Normal: F =0.9 CLT= 9 L/hr • Dose = 25 mg every 24 hr • Polymorphism : F= 0.95 CLT =4.75 L/hr • Dose = ? mg / 24 hr

50. Drug B • Normal: F =0.1 CLT= 81 L/hr • Dose = 200 mg every 24 hr • Polymorphism: F= 0.18 CLT = 73.8 L/hr • Dose = ? mg / 24 hr