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.
Muralidharan
G
G
College of Pharmacy, University of Saskatchewan, Saskatoon, Canada.
Hawes
E M
EM
McKay
G
G
Midha
K K
KK
D000818:Animals; D019389:Cytochrome P-450 CYP2D6; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006863:Hydrogen-Ion Concentration; D008694:Methamphetamine / Q000031:analogs & derivatives* / Q000652:urine; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010084:Oxidation-Reduction; D011802:Quinidine / Q000008:administration & dosage / Q000494:pharmacology*; D011803:Quinine / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew
D065607:Cytochrome P-450 Enzyme Inhibitors; D008694:Methamphetamine; D003577:Cytochrome P-450 Enzyme System; D011803:Quinine; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; D011802:Quinidine; C005157:methoxyphenamine