INHIBITION AND INDUCTION OF CYTOCHROME P4502E1-CATALYZED OXIDATION BYISONIAZID IN HUMANS

We studied the effect of isoniazid administration on the cytochrome P4 502E1-catalyzed elimination of chlorzoxazone and acetaminophen. Isonia zid, 300 mg daily, was administered for 7 days to a group of 10 volunt eer slow acetylators. Acetaminophen, 500 mg, and chlorzoxazone, 750 mg , were administered on separate occasions before isoniazid, during the period of isoniazid administration, and after the discontinuation of isoniazid. Isoniazid inhibited the clearance of chlorzoxazone by 58%, as assessed from plasma data, and inhibited the formation of acetamino phen thioether metabolites (a measure of the formation of the hepatoto xin N-acetyl-p-benzoquinone imine and catechol oxidative metabolites o f acetaminophen, as determined from their recovery in urine, by 63% an d 49%, respectively. Two days after the discontinuation of isoniazid, the clearance of chlorzoxazone was increased over the value before iso niazid by 56%. Acetaminophen thioether but not catechol metabolites we re increased by 56% 1 day after the discontinuation of isoniazid and h ad returned to the pre-isoniazid value 3 days after the discontinuatio n of isoniazid. We conclude that the time course of the interaction wi th regard to chlorzoxazone elimination and formation is compatible wit h an inhibition-induction effect of isoniazid on cytochrome P4502E1. T he mechanism of this biphasic effect is probably induction by protein stabilization, which results in inhibition of catalytic activity while isoniazid is present.