Designer drugs that are potent inhibitors of CYP2D6

Some abused drugs are substrates of CYP2D6 (e.g., paramethoxyamphetamine, methylenedioxy-methamphetamine). CYP2D6 inhibition by concurrently used drugs of abuse could potentiate such drugs and increase acute toxicity. Ten designer drugs were tested as inhibitors of CYP2D6. Only 1-methyl-4-phenyl-4-propionoxypiperidine (MPPP) and 1-[2-phenylethyl]-4-phenyl-4-acetoxypiperidine (PEPAP) interacted significantly (Ki 1.6 microM and 0.3 microM, respectively). Both are synthetic analogues of meperidine sold as "synthetic heroin." No CYP2D6-mediated metabolites were detected for either compound. Concurrent oral use of CYP2D6 substrates with MPPP and PEPAP may represent a kinetic drug interaction risk, but this risk must be confirmed clinically.