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1. Mol Diagn Ther. 2012 Feb 1;16(1):43-53. doi: 10.2165/11597930-000000000-00000.

Pharmacogenomics of Codeine, Morphine, and Morphine-6-Glucuronide: Model-Based
Analysis of the Influence of CYP2D6 Activity, UGT2B7 Activity, Renal Impairment,
and CYP3A4 Inhibition.

Eissing T, Lippert J, Willmann S.

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

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.

PMID: 22352453 [PubMed - in process]