# hepatic clearance

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### Seminar on Hepatic clearance:

Seminar on Hepatic clearance By Pradeep Kumar Koyi M.Pharm Pharmaceutics 1

### HEPATIC CLEARANCE:

HEPATIC CLEARANCE The difference in the systemic clearance and renal clearance is often termed as hepatic clearance. For certain drugs non renal clearance is equal to hepatic clearance (i.e., clearance of drug in blood by liver). 2

### Slide 3:

For drugs that are virtuallly completely metabolised the the renal clearance is negligible, we can assume that systemic clearance is equal to hepatic clearance and is given by Cl H = hepatic clearance Q H = hepatic blood flow 1.0 to 1.5 L/min E = hepatic extraction ratio ranges from 0 to 1 3 Cl H = Q H E

### HEPATIC CLEARANCE:

4 HEPATIC CLEARANCE Q x C A Q x C V Q ( C A - C V ) Rate of Extraction 1. Mass Balance

### HEPATIC CLEARANCE:

5 HEPATIC CLEARANCE Extraction Ratio 2. Mass Balance Normalized to Rate of Entry 1 1 - E E

### HEPATIC CLEARANCE:

6 HEPATIC CLEARANCE Clearance 3. Mass Balance Normalized to C A Q Q(1 – E) Q x E

### Slide 7:

7 Recall that Cl = QE; hence Cl H = hepatic clearance Q H = hepatic blood flow E = hepatic extraction ratio Q H - from 1.0 to 1.5 L/min E – ranges from 0 to 1 Cl H = Q H E

### Slide 8:

8 The maximum value of Cl H is hepatic blood flow. Thus, if the non-renal clearance of a drug exceeds Q H , some form of non-hepatic metabolism or non-hepatic elimination processes takes place and that non-renal clearance is not equal to hepatic clearance.

### Slide 9:

9 Example: (labetalol) CL T = 2.344 L/min CL R = 0.08 L/min V ss = 685 L t 1/2 = 6 hr Can the nonrenal clearance be attributed solely to hepatic elimination?

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10 CL H = Q H E Suggests that CL H ~ Q H Actually h Q H = i E

### VENOUS EQUILIBRIUM MODEL:

11 VENOUS EQUILIBRIUM MODEL QC in QC out Elimination

### SINUSOIDAL MODEL:

12 SINUSOIDAL MODEL QC in QC out Elimination

### Slide 13:

13 Intrinsic hepatic clearance: The ability of the liver to remove xenobiotic from the blood in the absence of other confounding factors (e.q., Q H ).

### Slide 14:

14 Since CL H = Q H E

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### Quantitative Assessment of Hepatic Clearance Assuming the Venous Equilibrium Model:

16 Quantitative Assessment of Hepatic Clearance Assuming the Venous Equilibrium Model

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19 Limits:

20 Limits:

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22 Limits:

23 Limits:

### Slide 24:

24 Compounds with a high CL int , are said to exhibit perfusion rate-limited elimination.

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25 From: Rowland M, Tozer TN. Clinical Pharmacokinetics: Concepts and Applications , 3 rd edition, 1995, p. 162

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26 HEPATIC EXTRACTION RATIO OF REPRESENTATIVE DRUGS Low (<0.3) Antipyrine Diazepam Phenylbutazone Theophylline Tolbutamide Warfarin High (>0.7) Lidocaine Meperidine Propoxyphene Propranolol Verapamil Intermediate: Quinidine

### Slide 27:

27 Consider the case of administering a constant infusion of a drug with the following conditions: CL int = 7.0 L/min, Q H = 1.0 L/min K o = 1.0 mg/min Assuming drug is eliminated completely via hepatic metabolism, what would the steady-state concentration be?

28

### Slide 29:

29 What if the pt developed CHF resulting in a 25% reduction in Q H ?

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30 In contrast, suppose we administer a low CL int ? CL int = 0.01 L/min, Q H = 1.0 L/min K 0 = 0.1 mg/min

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31 What if Q H were reduced by 25%

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32 FIRST-PASS EFFECT HEART GUT LIVER BODY

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33 HEART GUT LIVER BODY

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34 HEART GUT LIVER BODY

### Slide 35:

35 HEART GUT LIVER BODY

### Slide 36:

36 HEART GUT LIVER BODY

### Slide 37:

37 HEART GUT LIVER BODY

### Slide 38:

38 If a drug is completely absorbed after oral administration, the fraction of the oral dose that reaches the systemic circulation ( F ) is given as F = 1 - E Remembering that

### Slide 39:

39 Q H >> CL int , F g 1 Q H << CL int , F g 0

40

### Slide 41:

41 Determination of CL int after oral dosing: Assumes: Drug is completely absorbed No extrahepatic metabolism System is stationary

### Slide 42:

42 Determination of CL int after oral dosing:

### Slide 43:

43 Determination of CL int after oral dosing:

### Slide 44:

44 Estimated in this fashion the CL int is often referred to as the oral clearance ( CL o ) For a high CL int drug:

### Slide 45:

45 Estimated in this fashion the CL int is often referred to as the oral clearance ( CL o ) For a low CL int drug:

### Slide 46:

46 Consider a high clearance drug (e.g., propranolol) after oral and IV dosing: CL int = 10 L/min, Q H = 1.5 L/min

### Slide 47:

47 What would happen to CL H is Q H were reduced to 1.0 L/min? What if drug were administered orally under these conditions?

48

### Slide 49:

49 How would a decrease in Q H affect this?

### Slide 50:

50 But what happens to AUC? For control conditions: When Q H is decreased:

### Slide 51:

51 IMPACT OF PROTEIN BINDING CL int = f ub CL uint

52

### Slide 53:

53 Effect of protein binding on warfarin clearance in the rat . Data from Yacobi A, Levy G. J Pharm Sci 64:1660, 1975.

### Slide 54:

54 Effect of protein binding on warfarin clearance in humans. Data from Routledge et al. Br J Clin Pharmacol 8:243, 1979.

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55 CL uint = 0.25 L/min Q H = 1.5 L/min f ub = 0.1 K 0 = 0.25 mg/min

### Slide 56:

56 CL uint = 0.25 L/min Q H = 1.5 L/min f ub = 0.1 K 0 = 0.25 mg/min

### Slide 57:

57 What if f ub = 0.2?

### Slide 58:

58 What if f ub = 0.2?

### Slide 59:

59 What happens to free concentration?

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61 Consider a high clearance drug iv: CL uint = 30 L/min Q H = 1.5 L/min f ub = 0.25 K 0 = 2 mg/min

### Slide 62:

62 Consider a high clearance drug iv: CL uint = 30 L/min Q H = 1.5 L/min f ub = 0.25 K 0 = 2 mg/min

### Slide 63:

63 What if f ub = 0.5?

### Slide 64:

64 What if f ub = 0.5?

### Slide 66:

66 What if f ub = 0.5?

### Slide 67:

67 What if f ub = 0.5?

### Slide 68:

68 Effect of displacement (D) of plasma protein binding on total and unbound concentrations of drug From: Rowland M, Tozer TN. Clinical Pharmacokinetics – Concepts and Applications , 3 rd edition

### Slide 69:

69 From: Rowland M, Tozer TN. Clinical Pharmacokinetics – Concepts and Applications , 3 rd edition

### Slide 70:

70 Effect of changes in the determinants of hepatic clearance on the concentration versus time curves 1.0 0.1 Blood Concentration E 0.1 CL int 0.167 L/min CL H 0.150 L/min Time 0.18 0.334 L/min 0.273 L/min

### Slide 71:

71 Effect of changes in the determinants of hepatic clearance on the concentration versus time curves 1.0 0.1 Blood Concentration Time

### Slide 72:

72 Effect of changes in the determinants of hepatic clearance on the concentration versus time curves 1.0 0.1 Blood Concentration E 0.90 CL int 13.7 L/min CL H 1.35 L/min Time 0.95 27.0 L/min 1.42 L/min

### Slide 73:

73 Effect of changes in the determinants of hepatic clearance on the concentration versus time curves 0.1 0.01 Blood Concentration Time

### Slide 74:

74 Effect of rifampin on the kinetics of warfarin after a single dose before (open circles) and after (closed circles) treatment with rifampin 600 mg/day. From: O’Reilly RA. Interaction of sodium warfarin and rifampin. Ann Intern Med 81:337-40, 1974.

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### Slide 76:

76 Effect of pentobarbital on alprenolol disposition. Alprenolol was administered before (O, closed, iv, open oral) and after 10 d of pentobarbital ( D ). Reproduced from Alvan G, et al. Clin Pharmacol Ther 22:316-321, 1977.

### Slide 77:

77 Effect of changes in the determinants of hepatic clearance on the concentration versus time curves 1.0 0.1 Blood Concentration E 0.1 Q H 1.50 L/min CL H 0.150 L/min Time 0.18 0.75 L/min 0.135 L/min

### Slide 78:

78 Effect of changes in the determinants of hepatic clearance on the concentration versus time curves 1.0 0.1 Blood Concentration Time

### Slide 79:

79 Effect of changes in the determinants of hepatic clearance on the concentration versus time curves 1.0 0.1 Blood Concentration E 0.90 Q H 1.50 L/min CL H 1.35 L/min Time 0.95 0.75 L/min 0.71 L/min

### Slide 80:

80 Effect of changes in the determinants of hepatic clearance on the concentration versus time curves 0.1 0.01 Blood Concentration Time

### Slide 81:

81 Propoxyphene’s CNS depression is enhanced when co-administered with ethanol. To assess the contribution of a pharmacokinetic interaction to this enhancement, propoxyphene was administered iv and po, with and without ethanol. The curves below illustrate the results. What is the mechanism of interaction? TIME Log [Propoxyphene] TIME Log [Propoxyphene] Propoxyphene alone Propoxyphene + ETOH

### Slide 82:

82 Complete the following graphs for a drug with a CL H = 20 mL/min/kg and one with a CL H = 1 mL/min/kg f up CL H f up AUC o

### Slide 83:

83 Complete the following graphs for a drug with a CL H = 20 mL/min/kg and one with a CL H = 1 mL/min/kg f up CL uint Q H CL H

### Slide 84:

84 Complete the following graphs for a drug with a CLH = 20 mL/min/kg and one with a CLH = 1 mL/min/kg f up CL uint

### Slide 85:

85 Complete the following graphs for a drug with a CLH = 20 mL/min/kg and one with a CLH = 1 mL/min/kg Q H CL H

### Slide 86:

86 E Q H f ub f ut CL T V ss t 1/2 AUC o High h n n High n i n High n n h

### Slide 87:

87 E Q H f ub f ut CL T V ss t 1/2 AUC o Low h n n Low n n h Low n h n n