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Pharmacogenomics of Codeine, Morphine, and Morphine-6-Glucuronide

Model-Based Analysis of the Influence of CYP2D6 Activity, UGT2B7 Activity, Renal Impairment, and CYP3A4 Inhibition

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Abstract

Background and Objective: The analgesic effect of codeine depends on the formation of the opioid metabolites morphine and morphine-6-glucuronide. Different factors have been shown or suspected to affect the safety and efficacy of codeine treatment. The objective of the current study is to assess and quantify the impact of important pharmacokinetic factors, using a mechanistic modeling approach.

Methods: By means of a generic modeling approach integrating prior physiologic knowledge, we systematically investigated the complex dependence of opioid exposure on cytochrome P450 2D6 and 3A4 (CYP2D6 and CYP3A4), and uridine diphosphate glucuronosyltransferase 2B7 (UGT2B7) activity, as well as renal function, by means of a virtual clinical trial.

Results: First, the known dominant role of CYP2D6 activity for morphine exposure was reproduced. Second, the model demonstrated that mild and moderate renal impairment and co-administration of CYP3A4 inhibitors have only minor influences on opioid exposure. Third, the model showed — in contrast to current opinion — that increased UGT2B7 activity is associated with a decrease in active opioid exposure.

Conclusion: Overall, the model-based analysis predicts a wide range of morphine levels after codeine administration and supports recent doubts about safe and efficacious use of codeine for analgesia in non-genotyped individuals.

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Acknowledgments

The authors acknowledge financial support by the Virtual Liver Initiative (www.virtual-liver.de <http://www.virtual-liver.de>), QuantPro Initiative (www.ptj.de/quantpro <http://www.ptj.de/quantpro>), FORSYS-Partner Initiative (www.forsys.net <http://www.forsys.net>), and Services@MediGrid Initiative (www.medigrid.de <http://www.medigrid.de>), partly funded by the German Federal Ministry of Research and Education (BmBF).

T.E., J.L., and S.W. are employees of Bayer Technology Services GmbH, the company that owns and commercializes the software platform used for the simulations described in the manuscript (PK-Sim® and MoBi®), as well as parent company stock owners.

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  1. Competence Center Systems Biology and Computational Solutions, Bayer Technology Services GmbH, Leverkusen, Germany

    Thomas Eissing, Jörg Lippert &  Stefan Willmann

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  1. Thomas Eissing
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Correspondence to Stefan Willmann.

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Eissing, T., Lippert, J. & Willmann, S. Pharmacogenomics of Codeine, Morphine, and Morphine-6-Glucuronide. Mol Diagn Ther 16, 43–53 (2012). https://doi.org/10.1007/BF03256429

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