Impairment of drug metabolism in man by allopurinol and nortriptyline.

Abstract

Normal medical students received either allopurinol or nortriptyline. To quantitate changes in rates of drug metabolism produced by allopurinol or nortriptyline administration, the plasma half-lives of antipyrine or bishydroxycoumarin were determined both before and 24 hours after the last dose of allopurinol or nortriptyline. Allopurinol and nortriptyline each markedly prolonged the plasma half-lives of antipyrine and bishydroxycoumarin; large individual variations in prolongation times were observed. In rats, allopurinol and nortriptyline each reduced the activity of hepatic microsomal drug-metabolizing enzymes and slightly lowered the level of cytochrome P-450. These results in rats support the interpretation that in man prolongation of antipyrine and bishydroxycoumarin half-lives after allopurinol or nortriptyline pretreatment is produced by reduced rates of drug biotransformation in liver microsomes. Lowering of the usual dose and close monitoring of blood levels of drugs given simultaneously with allopurinol or nortriptyline are recommended to avoid the potential danger of drug accumulation due to slowed metabolism.