Quinidine but not quinine inhibits in man the oxidative metabolic routes of methoxyphenamine which involve debrisoquine 4-hydroxylase.
Healthy male volunteers (n = 13) took a single oral dose of 60.3 mg of methoxyphenamine HCl with and without prior administration of either quinidine (250 mg as bisulphate salt) or its diastereomer quinine (300 mg as sulphate salt). Methoxyphenamine and its N-desmethyl, O-desmethyl and aromatic 5-hydroxy metabolites were quantified in the 0-32 h urine. The oxidative routes of methoxyphenamine metabolisms which had been previously shown to involve debrisoquine 4-hydroxylase, namely O-demethylation and 5-hydroxylation were both significantly inhibited by quinidine in the 12 extensive metabolizers. The inhibition was selective in that N-demethylation which does not involve this isozyme was not affected by quinidine. In all but one of these volunteers the methoxyphenamine/O-desmethylmethoxyphenamine ratio changed such that extensive metabolizers could be classified as poor metabolizers due to quinidine pretreatment. No marked change occurred in the renal excretion of methoxyphenamine and its three metabolites either in the extensive metabolizers because of quinine pretreatment or in the poor metabolizer because of treatment with either quinidine or quinine. Thus in the extensive metabolizer phenotype it was demonstrated in one study that enzyme inhibition of quinidine was selective in terms of the metabolic pathways inhibited as well as stereoselective with respect to the inhibitor.
Muralidharan
G
G
College of Pharmacy, University of Saskatchewan, Saskatoon, Canada.
Hawes
E M
EM
McKay
G
G
Korchinski
E D
ED
Midha
K K
KK
D000328:Adult; D019389:Cytochrome P-450 CYP2D6; D065607:Cytochrome P-450 Enzyme Inhibitors; D006801:Humans; D008297:Male; D008694:Methamphetamine / Q000031:analogs & derivatives* / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D010084:Oxidation-Reduction; D011802:Quinidine / Q000494:pharmacology*; D011803:Quinine / Q000494:pharmacology*
D065607:Cytochrome P-450 Enzyme Inhibitors; D008694:Methamphetamine; D011803:Quinine; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; D011802:Quinidine; C005157:methoxyphenamine