Vol. 280, Issue 3, 1374-1382, 1997

Effect of Cytochrome P450 2D1 Inhibition on Hydrocodone Metabolism and its Behavioral Consequences in Rats¹

D. M. Tomkins, S. V. Otton, N. Joharchi, N-Y. Li, R. F. Balster, R. F. Tyndale and E. M. Sellers

Addiction Research Foundation, 33 Russell Street, Toronto, Ontario, M5S 2S1 (D.M.T., S.V.O., N.J., N.Y.L., R.F.T., E.M.S.) and Departments of Pharmacology, Medicine and Psychiatry, University of Toronto, Toronto, Ontario, Canada (R.F.T., E.M.S.) and Center for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, Virginia (R.B.)

Humans that lack cytochrome P450 2D6 (CYP2D6) activity may have an altered risk of drug dependence or abuse because this enzyme is important in the metabolism of some drugs of abuse, including hydrocodone. In rats, hydrocodone conversion to hydromorphone is catalyzed by CYP2D1, the rat homolog of the human CYP2D6. To determine the impact of impaired hydromorphone formation on the behavioral effects of the parent compound, hydrocodone-induced analgesia and hyperactivity, hydrocodone discrimination and self-administration were examined in male Wistar rats, with or without pretreatment with CYP2D1 inhibitors (quinine and budipine). In vivo, quinine (20 mg/kg) and budipine (10 mg/kg) produced a marked suppression in brain and plasma hydromorphone levels detected after the peripheral administration of hydrocodone, thus confirming that the doses used suppressed CYP2D1 activity. In contrast, CYP2D1 inhibition had no impact on the analgesic or discriminative stimulus effects of hydrocodone, nor did this type of manipulation alter hydrocodone self-administration. The effects of quinine on the locomotor activating effects of hydrocodone were subtle at best. Because inhibition of CYP2D1 in this rat strain is proposed to be a useful animal counterpart for studying the impact of CYP2D6 polymorphism in humans, these data suggest that differences in CYP2D6 phenotype will have limited influence on the drug response to hydrocodone after nonoral administration. This has recently been verified in a study showing that inhibition of hydrocodone biotransformation to hydromorphone does not affect measures of abuse liability. Therefore, hydrocodone's behavioral effects are most likely attributable to its own intrinsic effects at mu opioid receptors.