Ethanol and Drug Metabolism

Pharmacokinetics

ethanol is rapidly and completely absorbed (V_D = 0.7 L/kg)

>90% of ethanol metabolism occurs in the liver in zero-order manner

amount of ethanol oxidized is proportional to body weight or liver weight

ethanol can induce metabolism involving cytochrome P-450 cyp 2E1

Acute Drug Interactions

(1) Ethanol affects phase I and phase II metabolism of many drugs

overproduction of acetate may enhance N-acetylation (e.g., acetylation of isoniazid)
utilization of NAD⁺ may inhibit UDP-glucuronidase (e.g., metabolism of morphine requires two NAD⁺)
glucose depletion may deplete cofactors requiring glucose for their production (e.g., UDP-glucuronidase)
ethanol directly affects some enzymes involved in drug metabolism (e.g., sulfonidase)
acetaldehyde forms adducts with glutothione

(2) Ethanol inhibits cytochrome P450 (phase I oxidation) by competitive and noncompetitive mechanisms

active site competition (e.g., acetominophen) or O₂ binding site competition (e.g., warfarin)

P-450 mediated metbolism of ethanol may cause a ß in availability of NADPH P-450 reductase for other drugs

can increase effective dose of drugs with large first pass effect

Chronic Drug Interactions

(1) Ethanol can cause the proliferation of ER and change the distribution of cytochrome P-450 (inducing cyp 2E1)

(2) Ethanol can induce P-450, increasing rate of metabolism

this can decrease the effectiveness of a drug or increase the rate of formation of toxic by-products

e.g., acetominophen (ß phase II reactions and Ý phase I reactions) – P-450 degradation pathway produces a dangerous electrophile

(3) Liver damage can lower hepatic blood flow and decreased metabolism

cirrhosis causes decreased blood flow due to portal shunting
e.g., lidocaine – high intrinsic clearance, so serum concentration determined by liver blood flow

(4) Liver damage can cause lowered albumin synthesis