Appetite suppressant drugs as inhibitors of human cytochromes P450:: In vitro inhibition of P450-2D6 by D- and L-fenfluramine, but not phentermine

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