APPETITE-SUPPRESSANT DRUGS AS INHIBITORS OF HUMAN CYTOCHROMES P450 - IN-VITRO INHIBITION OF P450-2D6 BY D-FENFLURAMINE AND L-FENFLURAMINE, BUT NOT PHENTERMINE

The activity of D-fenfluramine, L-fenfluramine, and phentermine as inh ibitors of five human cytochromes P450 was evaluated using human Liver microsomes in vitro. AU three compounds produced negligible inhibitio n of P450-1A2, -2C9, -2E1, and -3A. Phentermine also did not inhibit P 450-2D6. However, D- and L-fenfluramine significantly inhibited P450-2 D6 activity as measured by dextromethorphan O-demethylation, with mean 50% inhibitory concentrations (15.1 mu M) within one order of magnitu de of that for fluoxetine (2.7 mu M). Findings from the in vitro assay are consistent with clinical studies showing significant inhibition o f desipramine clearance by coadministration of fenfluramine.