CYP3A5*3 affects plasma disposition of noroxycodone and dose escalation in cancer patients receiving oxycodone

J Clin Pharmacol. 2011 Nov;51(11):1529-38. doi: 10.1177/0091270010388033. Epub 2011 Jan 5.

Abstract

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.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Aged
  • Asian Continental Ancestry Group
  • Cytochrome P-450 CYP2D6 / genetics
  • Cytochrome P-450 CYP2D6 / metabolism
  • Cytochrome P-450 CYP3A / genetics*
  • Cytochrome P-450 CYP3A / metabolism
  • Delayed-Action Preparations
  • Female
  • Humans
  • Male
  • Middle Aged
  • Morphinans / blood*
  • Neoplasms / blood*
  • Neoplasms / drug therapy
  • Neoplasms / enzymology
  • Neoplasms / genetics
  • Oxycodone / administration & dosage*
  • Oxycodone / blood
  • Oxycodone / pharmacokinetics
  • Oxymorphone / blood
  • Polymorphism, Genetic
  • Receptors, Opioid, mu / genetics
  • Receptors, Opioid, mu / metabolism

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Delayed-Action Preparations
  • Morphinans
  • OPRM1 protein, human
  • Receptors, Opioid, mu
  • noroxycodone
  • Oxymorphone
  • Oxycodone
  • CYP3A5 protein, human
  • Cytochrome P-450 CYP2D6
  • Cytochrome P-450 CYP3A