Metabolism

Question 1

Hepatic Clearance

Answer 1

Clh = QhE

E = Function of ALL enzyme activities and dependent on Q, Cli, and fp
Qh = Liver blood flow
Clh = Hepatic clearance

Clh = Qh [(fp * Cli) / (Qh + fp * Cli)]

fp = free fraction (unbound to plasma proteins)

Question 2

Cli

Answer 2

• Unbound intrinsic clearance
• Indicates maximal ability of liver to irreversibly remove unbound drug by all pathways in absence of flow limiation
• Distinct characteristics of individual drugs

Question 3

Classifications

Answer 3

1. Low Extraction Ratio Drugs

2. High Extraction Ratio Drugs

Question 4

Low Extraction Ratio Drugs

Answer 4

-fp * Cli &laquo_space;Qh
-Clh = fp * Cli (approximately)
-Blood flow has limited effect on hepatic clearance, but it is still dependent on fp & Cli
-Clh is enzyme-rate limited
EX: antipyrine, warfarin, valproic acid, theophylline, salicylic acid, phenobarbital, diazepam

Question 5

High Extraction Ratio Drugs

Answer 5

• fp * Cli&raquo_space; Qh
• Clh = Qh (approximately)
• Hepatic clearance largely depends on the liver blood flow (blow flow is rate limited)
• EX: Propranolol, nitroglycerin, morphine, alprenolol, desipramine

Question 6

Hepatic Bioavailability

Answer 6

• Some drugs, route of administration affects metabolic rate
• Drugs given parentally, transdermally, or inhalation will distribute systemically before entering liver
• Drugs given orally go directly to liver first
• Drugs that are highly metabolized have decreased systemic availability

Question 7

Hepatic Bioavailability Equations

Answer 7

Bioavailability = 1 - Eh

Fh = Qh / (Qh + fp * Cli)

Question 8

Low E Drugs

Answer 8

• Fh approaches 1 (100%)

- Some change in Qh, fp, ad Cli will NOT alter Fh significantly

Question 9

High E Drugs

Answer 9

• Fh = Qh / (fp * Cli) (approximately)

- Any change in Qh, fp, and Cli WILL effect Fh