CYP3A5*3 Affects Plasma Disposition of Noroxycodone and Dose Escalation in Cancer Patients Receiving Oxycodone

Naito, Takafumi; Takashina, Yoshiaki; Yamamoto, Keisuke; Tashiro, Masaki; Ohnishi, Kazunori; Kagawa, Yoshiyuki; Kawakami, Junichi

doi:10.1177/0091270010388033

Cited by 44 publications

(30 citation statements)

References 39 publications

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“…Among these is oxycodone (Naito et al, 2011), and the data reported in this study are consistent with the oxycodone clinical data. However, previously reported data showed that recombinant CYP3A5 had a higher intrinsic clearance for oxycodone N-demethylation than CYP3A4 (Lalovic et al, 2004).…”

Section: Discussionsupporting

confidence: 90%

Relative Contributions of Cytochrome CYP3A4 Versus CYP3A5 for CYP3A-Cleared Drugs Assessed In Vitro Using a CYP3A4-Selective Inactivator (CYP3cide)

et al. 2014

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Metabolism by cytochrome P4503A (CYP3A) is the most prevalent clearance pathway for drugs. Designation of metabolism by CYP3A commonly refers to the potential contribution by one or both of two enzymes, CYP3A4 and CYP3A5. The metabolic turnover of 32 drugs known to be largely metabolized by CYP3A was examined in human liver microsomes (HLMs) from CYP3A5 expressers (*1/*1 genotype) and nonexpressers (*3/*3 genotype) in the presence and absence of ketoconazole and CYP3cide (a selective CYP3A4 inactivator) to calculate the contribution of CYP3A5 to metabolism. Drugs with the highest contribution of CYP3A5 included atazanavir, vincristine, midazolam, vardenafil, otenabant, verapamil, and tacrolimus, whereas 17 of the 32 tested showed negligible CYP3A5 contribution. For specific reactions in HLMs from *1/*1 donors, CYP3A5 contributes 55% and 44% to midazolam 19-and 4-hydroxylation, 16% to testosterone 6b-hydroxylation, 56% and 19% to alprazolam 19-and 4-hydroxylation, 10% to tamoxifen N-demethylation, and 58% to atazanavir p-hydroxylation.Comparison of the in vitro observations to clinical pharmacokinetic data showed only a weak relationship between estimated contribution by CYP3A5 and impact of CYP3A5 genotype on oral clearance, in large part because of the scatter in clinical data and the low numbers of study subjects used in CYP3A5 pharmacogenetics studies. These data should be useful in guiding which drugs should be evaluated for differences in pharmacokinetics and metabolism between subjects expressing CYP3A5 and those who do not express this enzyme.

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Section: Discussionsupporting

confidence: 90%

Relative Contributions of Cytochrome CYP3A4 Versus CYP3A5 for CYP3A-Cleared Drugs Assessed In Vitro Using a CYP3A4-Selective Inactivator (CYP3cide)

et al. 2014

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“…These results are consistent with the in vitro findings that CYP2C19 and UGT1A1 play a minor role in the overall clearance from the body. While CYP3A enzymes, especially CYP3A4, are clearly important in the metabolism of axitinib, the lack of correlation of pharmacokinetic variability with specific genotypes of CYP3A is consistent with the lack of phenotype-genotype correlations reported for other CYP3A substrates such as diltiazem, midazolam, nifedipine, and oxycodone (Floyd et al, 2003;Kharasch et al, 2007;Tomalik-Scharte et al, 2008;Naito et al, 2011;Haas et al, 2013;Zheng et al, 2013), where the pharmacokinetic variability can be attributed to the inherent range of CYP3A4 expression in the population, regardless of polymorphism. Additionally, investigations of pharmacokinetic variability seen in the clinic for axitinib, in lieu of the putative in vitro data supporting the prominent CYP3A4 role in axitinib clearance, include CYP3A4*22 polymorphism assessment from the collected genotyping samples.…”

Section: Discussionsupporting

confidence: 54%

In Vitro Kinetic Characterization of Axitinib Metabolism

Zientek

Goosen

Tseng

et al. 2015

Drug Metabolism and Disposition

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, respectively. Using a CYP3A4-specific inhibitor (Cyp3cide) in liver microsomes expressing CYP3A5, 66% of the axitinib intrinsic clearance was attributable to CYP3A4 and 15% to CYP3A5. Axitinib N-glucuronidation was primarily catalyzed by UDPglucuronosyltransferase (UGT) UGT1A1, which was verified by chemical inhibitors and UGT1A1 null expressers, with lesser contributions from UGTs 1A3, 1A9, and 1A4. The K m and V max values describing the formation of the N-glucuronide in HLM or rUGT1A1 were 2.7 mM or 0.75 mM and 8.9 or 8.3 pmol·min 21 ·mg 21 , respectively. In summary, CYP3A4 is the major enzyme involved in axitinib clearance with lesser contributions from CYP3A5, CYP2C19, CYP1A2, and UGT1A1.

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“…Conversely, another clinical study of 76 motherinfant breast feeding pairs found mothers carrying at least one copy of the ABCB1 2677T variant had an increased risk of experiencing oxycodone-induced sedation themselves (114). Yet another clinical study found that cancer patients with the C3435T polymorphism of ABCB1 had little effect on the plasma disposition of oxycodone (115). The clinical implications of these variant alleles on P-gp function need further investigations to decipher their impact on opioids that are Pgp substrates.…”

Section: Oxycodonementioning

confidence: 99%

“…As with morphine, there does not appear to be a clear consensus on the role of ABCB1 polymorphisms in the PK and PD of oxycodone (113)(114)(115), fentanyl (132)(133)(134), or methadone (155-162, 164, 165). The reasons behind this apparent lack of clarity may be complex, and possibly involve the geographic distribution of patients enrolled as well as the polymorphisms selected for investigation.…”

Section: Transporter Polymorphismsmentioning

confidence: 99%

Transporter-Mediated Disposition of Opioids: Implications for Clinical Drug Interactions

et al. 2015

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Opioid-related deaths, abuse, and drug interactions are growing epidemic problems that have medical, social, and economic implications. Drug transporters play a major role in the disposition of many drugs, including opioids; hence they can modulate their pharmacokinetics, pharmacodynamics and their associated drug-drug interactions (DDIs). Our understanding of the interaction of transporters with many therapeutic agents is improving; however, investigating such interactions with opioids is progressing relatively slowly despite the alarming number of opioids-mediated DDIs that may be related to transporters. This review presents a comprehensive report of the current literature relating to opioids and their drug transporter interactions. Additionally, it highlights the emergence of transporters that are yet to be fully identified but may play prominent roles in the disposition of opioids, the growing interest in transporter genomics for opioids, and the potential implications of opioid-drug transporter interactions for cancer treatments. A better understanding of drug transporters interactions with opioids will provide greater insight into potential clinical DDIs and could help improve opioids safety and efficacy.

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CYP3A5*3 Affects Plasma Disposition of Noroxycodone and Dose Escalation in Cancer Patients Receiving Oxycodone

Cited by 44 publications

References 39 publications

Relative Contributions of Cytochrome CYP3A4 Versus CYP3A5 for CYP3A-Cleared Drugs Assessed In Vitro Using a CYP3A4-Selective Inactivator (CYP3cide)

Relative Contributions of Cytochrome CYP3A4 Versus CYP3A5 for CYP3A-Cleared Drugs Assessed In Vitro Using a CYP3A4-Selective Inactivator (CYP3cide)

In Vitro Kinetic Characterization of Axitinib Metabolism

Transporter-Mediated Disposition of Opioids: Implications for Clinical Drug Interactions

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