Journal
JOURNAL OF CLINICAL PHARMACOLOGY
Volume 51, Issue 11, Pages 1529-1538Publisher
WILEY
DOI: 10.1177/0091270010388033
Keywords
Oxycodone; genetic polymorphism; dose escalation; metabolite; cancer pain
Categories
Funding
- Japanese Ministry of Education, Culture, Sports, Science and Technology
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The aim of this study was to evaluate the plasma dispositions of oxycodone and its demethylates and dose escalation based on genetic polymorphisms of CYP2D6, CYP3A5, ABCB1, and OPRM1 in cancer patients receiving oxycodone. Sixty-two Japanese cancer patients receiving oxycodone extended-release tablets were enrolled. Predose plasma concentrations (C-12) of oxycodone, noroxycodone, and oxymorphone were determined at the titrated dose. Daily oxycodone escalation rate was evaluated as the opioid escalation index (OEI). Genetic variants did not significantly alter oxycodone C-12. Oxymorphone C-12 and its ratio to oxycodone C-12 were significantly higher in CYP2D6 extensive metabolizers than in intermediate metabolizers but did not affect dose escalation. In contrast, noroxycodone C-12 and its ratio to oxycodone C-12 were significantly higher in the CYP3A5*1 carrier group than in the *3/*3 group. The OEI was significantly higher in the CYP3A5*3/*3 group than in the *1 carrier group. No significant difference was observed in the OEI in the other genetic variants. Noroxycodone C-12 was higher in the dose escalation group as compared to the nonescalation group and significantly affected the incidence of dose escalation. In conclusion, CYP3A5*3 altered the plasma disposition of noroxycodone, which was inversely affecting the dose escalation in cancer patients receiving oxycodone.
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