Metabolism of methoxyphenamine in extensive and poor metabolizers of debrisoquin

Abstract

Urine and plasma concentrations of methoxyphenamine (MP) and 3 of its metabolites were determined after a single oral 60.3 mg dose of MP hydrochloride to healthy subjects of known debrisoquin (D) phenotype. Urine was collected from 5 extensive (EM) and 5 poor (PM) metabolizers of D for 12 h and analyzed after treatment with .beta.-glucuronidase/sulfatase. There were marked interphenotype differences in the total urinary excretion of O-demethylmethoxyphenamine (ODMP) and 5-hydroxymethoxyphenamine (5HMP), as well as in MP/ODMP and MP/5HMP ratios. The urinary output of N-demethylmethoxyphenamine (NDMP) or MP/NDMP ratios showed no interphenotype differences. Plasma data from 2 EM and 2 PM showed that the mean values for maximum concentration, t1/2, and total AUC for MP were 2-, 3- and 6-fold greater, respectively, in PM than in EM. The plasma levels of ODMP and 5HMP were higher in EM than in PM, whereas the converse was true for NDMP. O-demethylation and aromatic 5-hydroxylation of MP are defective in PM of D, resulting in increased MP and NDMP plasma levels. The form of cytochrome P-450 involved in the N-demethylation of MP is different from that responsible for O-demethylation and aromatic 5-hydroxylation.