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Effect of Genetic Polymorphisms in Cytochrome P450 (CYP) 2C9 and CYP2C8 on the Pharmacokinetics of Oral Antidiabetic Drugs

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Abstract

Type 2 diabetes mellitus affects up to 8% of the adult population in Western countries. Treatment of this disease with oral antidiabetic drugs is characterised by considerable interindividual variability in pharmacokinetics, clinical efficacy and adverse effects. Genetic factors are known to contribute to individual differences in bioavailability, drug transport, metabolism and drug action. Only scarce data exist on the clinical implications of this genetic variability on adverse drug effects or clinical outcomes in patients taking oral antidiabetics.

The polymorphic enzyme cytochrome P450 (CYP) 2C9 is the main enzyme catalysing the biotransformation of sulphonylureas. Total oral clearance of all studied sulphonylureas (tolbutamide, glibenclamide [glyburide], glimepiride, glipizide) was only about 20% in persons with the CYP2C9*3/*3 genotype compared with carriers of the wild-type genotype CYP2C9*1/*1, and clearance in the heterozygous carriers was between 50% and 80% of that of the wild-type genotypes. For reasons not completely known, the resulting differences in drug effects were much less pronounced. Nevertheless, CYP2C9 genotype-based dose adjustments may reduce the incidence of adverse effects. The magnitude of how doses might be adjusted can be derived from pharmacokinetic studies.

The meglitinide-class drug nateglinide is metabolised by CYP2C9. According to the pharmacokinetic data, moderate dose adjustments based on CYP2C9 genotypes may help in reducing interindividual variability in the antihyperglycaemic effects of nateglinide. Repaglinide is metabolised by CYP2C8 and, according to clinical studies, CYP2C8*3 carriers had higher clearance than carriers of the wild-type genotypes; however, this was not consistent with in vitro data and therefore further studies are needed. CYP2C8*3 is closely linked with CYP2C9*2.

CYP2C8 and CYP3A4 are the main enzymes catalysing biotransformation of the thiazolidinediones troglitazone and pioglitazone, whereas rosiglitazone is metabolised by CYP2C9 and CYP2C8. The biguanide metformin is not significantly metabolised but polymorphisms in the organic cation transporter (OCT) 1 and OCT2 may determine its pharmacokinetic variability.

In conclusion, pharmacogenetic variability plays an important role in the pharmacokinetics of oral antidiabetic drugs; however, to date, the impact of this variability on clinical outcomes in patients is mostly unknown and prospective studies on the medical benefit of CYP genotyping are required.

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Acknowledgements

Financial support for this work was given by the German Ministry of Education and Research (GG 9845/5 and 03/4507) and by the German Research Foundation (KI 842/5-1). The authors have no conflicts of interest that are directly relevant to the content of this review.

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Authors and Affiliations

  1. Institute of Clinical Pharmacology, University Medical Center Charité, Humboldt University, Berlin, Germany

    Julia Kirchheiner, Ivar Roots & Mark Goldammer

  2. Department of Pharmacology, University of Cologne, Köln, Germany

    Julia Kirchheiner

  3. CENiMED GmbH, Berlin, Germany

    Ivar Roots & Mark Goldammer

  4. Jerini AG, Berlin, Germany

    Bernd Rosenkranz

  5. Department of Clinical Pharmacology, Georg August University Göttingen, Göttingen, Germany

    Jürgen Brockmöller

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Kirchheiner, J., Roots, I., Goldammer, M. et al. Effect of Genetic Polymorphisms in Cytochrome P450 (CYP) 2C9 and CYP2C8 on the Pharmacokinetics of Oral Antidiabetic Drugs. Clin Pharmacokinet 44, 1209–1225 (2005). https://doi.org/10.2165/00003088-200544120-00002

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