EFFECT OF CYTOCHROME-P450 2D1 INHIBITION ON HYDROCODONE METABOLISM AND ITS BEHAVIORAL CONSEQUENCES IN RATS

Humans that lack cytochrome P450 2D6 (CYP2D6) activity may have an alt ered risk of drug dependence or abuse because this enzyme is important in the metabolism of some drugs of abuse, including hydrocodone. In r ats, hydrocodone conversion to hydromorphone is catalyzed by CYP2D1, t he rat homolog of the human CYP2D6. To determine the impact of impaire d hydromorphone formation on the behavioral effects of the parent comp ound, hydrocodone-induced analgesia and hyperactivity, hydrocodone dis crimination and self-administration were examined in male Wistar rats, with or without pretreatment with CYP2D1 inhibitors (quinine and budi pine). In vivo, quinine (20 mg/kg) and budipine (10 mg/kg) produced a marked suppression in brain and plasma hydromorphone levels detected a fter the peripheral administration of hydrocodone, thus confirming tha t the doses used suppressed CYP2D1 activity. In contrast, CYP2D1 inhib ition had no impact on the analgesic or discriminative stimulus effect s of hydrocodone, nor did this type of manipulation alter hydrocodone self-administration. The effects of quinine on the locomotor activatin g effects of hydrocodone were subtle at best, Because inhibition of CY P2D1 in this rat strain is proposed to be a useful animal counterpart for studying the impact of CYP2D6 polymorphism in humans, these data s uggest that differences in CYP2D6 phenotype will have limited influenc e on the drug response to hydrocodone after nonoral administration. Th is has recently been verified in a study showing that inhibition of hy drocodone biotransformation to hydromorphone does not affect measures of abuse liability. Therefore, hydrocodone's behavioral effects are mo st likely attributable to its own intrinsic effects at mu opioid recep tors.