d-Propoxyphene is a Potent Inhibitor of Debrisoquine, but Not S-Mephenytoin 4-Hydroxylation In Vivo

Abstract

The debrisoquine and S-mephenytoin 4-hydroxylation phenotyping tests were performed in 14 healthy subjects. All were extensive metabolizers of both drugs. After at least 4 weeks, they received a 150 mg tablet of d-propoxyphene and 5 h later the debrisoquine-mephenytoin test was repeated. This single dose of d-propoxyphene caused no change in mephenytoin S/R ratio, but increased the debrisoquine metabolic ratio (MR) in each subject (p < 0.025). The four subjects with a relatively high MR (5.1-8.3) in the first test had an MR of debrisoquine in the second test ranging between 22 and 40, falsely classifying them as "poor metabolizers" of debrisoquine. This shows that d-propoxyphene is a potent inhibitor of debrisoquine, but not of S-mephenytoin 4-hydroxylase in vivo. A previous in vitro study has shown that d-propoxyphene inhibits the hydroxylation of desipramine, which is a substrate of the debrisoquine hydroxylase.