Quinine is a more potent inhibitor than quinidine in rat of the oxidative metabolic routes of methoxyphenamine which involve debrisoquine 4-hydroxylase.

1. Lewis rats (n = 7 or 8) were dosed with methoxyphenamine with and without prior administration of various doses of either quinine or its diastereomer quinidine. Methoxyphenamine and its N-desmethyl, O-desmethyl and aromatic 5-hydroxy metabolites were quantified in 0-24 h urine. 2. The oxidative routes of methoxyphenamine metabolism which had been previously shown to involve the debrisoquine/sparteine isoenzyme, namely O-demethylation and 5-hydroxylation, were both significantly inhibited by quinine. The inhibition was selective in that N-demethylation which does not involve this isoenzyme was not affected by quinine. 3. Quinidine which had been previously shown at a relatively high dose (80 mg/kg) to affect the three metabolic routes of methoxyphenamine in a similar fashion was ineffective in this regard at a 25 mg/kg dose. Quinine more effectively inhibited the O-demethylation and 5-hydroxylation of methoxyphenamine than did quinidine, and its inhibition was marked at the lowest dose examined, 12.5 mg/kg. 4. As quinidine is a more potent inhibitor than quinine of debrisoquine 4-hydroxylase in man, the rat should be used only with full realization of its limitations when investigating substrates metabolized by this isoenzyme.