Abstract
Enzymatic conversion of hydrocodone to hydromorphone is catalyzed by cytochrome P450 2D6, which is inactive in about 7% of Caucasians [poor metabolizers (PMs)] and can be inhibited by quinidine pretreatment in the remainder [extensive metabolizers (EMs)]. If hydromorphone, having a substantially higher μ-receptor affinity than hydrocodone, contributes importantly to the physiological and subjective effects of oral hydrocodone, then PMs should be less responsive to the same doses, and quinidine pretreatment should cause EMs to temporarily respond as PMs. Seventeen EMs and 8 PMs who previously responded positively to hydromorphone s.c. received placebo and hydrocodone (10 mg, 15 mg and 22.5 mg p.o.) and were retested with their favorite dose after placebo or quinidine (100 mg) pretreatment; physiological and subjective measures were collected at base line and four times after drug administration, and urine was collected for 8 hr. EMs and PMs were equally responsive to oral hydrocodone, and quinidine had no consistent effect on their responses, even though quinidine abolished the pre-existing metabolic differences in hydromorphone production, as measured in urine. These data suggest only a small role of hydromorphone in eliciting abuse-related responses to oral hydrocodone.
Footnotes
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Send reprint requests to: Edward M. Sellers, M.D., Ph.D., Department of Pharmacology, 1 King’s College Circle, Toronto, Ontario, Canada M5S 2S1.
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↵1 This work was supported in part by National Institute on Drug Abuse Grant DA06889.
- Abbreviations:
- ARCI
- Addiction Research Center Inventory
- CYP
- cytochrome P450
- EM
- extensive metabolizer
- MBG
- morphine-benzedrine group
- MR
- metabolic ratio
- PM
- poor metabolizer
- Received April 29, 1996.
- Accepted November 5, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
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