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Impact of genetic variation in CYP2C19, CYP2D6, and CYP3A4 on oxycodone and its metabolites in a large database of clinical urine drug tests

The Pharmacogenomics Journal volume 22, pages 25–32 (2022)Cite this article

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Abstract

Urine drug testing (UDT) is a tool for monitoring drug use, including oxycodone. While variation in cytochrome P450 (CYP) genes is known to alter oxycodone metabolism, its impact on UDT results of oxycodone and its metabolites has not been well-studied. Here, multivariate analysis was performed on retrospective UDT results of 90,379 specimens collected from 14,684 genotyped patients prescribed oxycodone. Genetic variation in CYP2D6 and CYP2C19 had a significant impact on oxymorphone/oxycodone ratios, with a 6.9-fold difference between CYP2D6 ultrarapid metabolizers (UMs) and poor metabolizers (PMs; p < 10−300) and a 1.6-fold difference between CYP2C19 UMs and PMs (p = 1.50 × 10−4). CYP2D6 variation also significantly impacted noroxycodone/oxycodone ratios (p = 6.95 × 10−38). Oxycodone-positive specimens from CYP2D6 PMs were ~5-fold more likely to be oxymorphone-negative compared to normal metabolizers. These findings indicate that multivariate analysis of UDT data may be used to reveal the real-world impact of genetic and non-genetic factors on drug metabolism.

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Fig. 1: Selection of patients and urine specimens for data analysis.
Fig. 2: Urinary oxymorphone/oxycodone (A) and noroxycodone/oxycodone (B) metabolic ratios by CYP2C19, CYP2D6, and CYP3A4 phenotypes.
Fig. 3: Marginal least square (LS) mean estimates of oxymorphone/oxycodone metabolic ratios for CYP2D6 (A) and CYP2C19 (B) phenotypes.
Fig. 4: Marginal least square (LS) mean estimates of noroxycodone/oxycodone metabolic ratios for CYP2D6 (A) and CYP3A4 (B) phenotypes.

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The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors thank Karthika Balasubramanian for critical review of the study design and results.

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Authors and Affiliations

  1. Millennium Health, LLC, San Diego, CA, USA

    Guang-dan Zhu, Penn Whitley, Leah LaRue, Brandon Adkins, Eric Dawson, Angela Huskey & Andria L. Del Tredici

  2. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA

    Edmund V. Capparelli

  3. Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA, USA

    Edmund V. Capparelli

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  1. Guang-dan Zhu
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Contributions

GZ, PW and AD conceptualized and designed the study including methodology. AH provided supervision and resources. GZ and PW performed data analysis. All authors contributed to interpretation of the results. GZ and AD took the lead on writing the paper. PW, LL, BA, ED and EC made substantial edits to the paper. All authors reviewed and approved the paper.

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Correspondence to Guang-dan Zhu.

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All authors except EC were employed by Millennium Health on a full-time basis at the time this study was completed. EC declares no competing financial interests.

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Zhu, Gd., Whitley, P., LaRue, L. et al. Impact of genetic variation in CYP2C19, CYP2D6, and CYP3A4 on oxycodone and its metabolites in a large database of clinical urine drug tests. Pharmacogenomics J 22, 25–32 (2022). https://doi.org/10.1038/s41397-021-00253-5

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