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Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays pp 1095–1123Cite as

Pharmacogenomics in Drug Metabolizing Enzymes and Transporters

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Abstract

The role of membrane transporters for the pharmacokinetic (PK) and pharmacodynamic (PD) properties of a drug is becoming evident in many aspects. Membrane transporters are major determinants for the absorption, distribution, and elimination of many drugs or at least of their more hydrophilic metabolites. Thereby, the overall effect of transporters is thoughtlessly underestimated, if only the systemic concentration of a drug is monitored clinically. The role of drug transporters on cellular and tissue distribution, especially with regard to the brain, the heart, the liver, the kidney, and other peripheral tissues seems to be of much higher importance. Unfortunately, the clinical investigation of tissue distribution phenomena requires the development of new techniques like PET (positron emission tomography), but already today, there is a clinical example of 11C-verapamil crossing the blood-brain barrier in the presence of a strong P-gp inhibitor (Eyal et al. 2010, pp. 579–585). Another impressive example is a significant and growing body of data showing a correlation between long-term response to imatinib chemotherapy in CML patients with functional OCT1 activity in the cancer cells (Engler et al. 2011, pp. 608–611) (imatinib is described as substrate of OCT1). More examples like this, illustrating the importance of transporters for cellular or tissue exposure, will be experienced in the near future with the development of PET-labeled transporter probe substrates and approaches of personalized medicine. The understanding of the role of pharmacogenetics in drug metabolism expanded greatly in the 1990s. This is mainly due to technological improvements in gene scanning and gene variant identification. The number of variant alleles identified for genes coding for drug metabolizing enzymes (DMEs) considerably increased in the early 2000s, and continues to increase. The clinical consequences – or at least genotyping-phenotyping relationships – of DME polymorphisms have not been demonstrated for all variants. Only those DME allele variants will be mentioned for which significant changes in enzyme activity have been found using probe drugs.

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  1. R&D Diabetes Division Leitung R&D FF Industriepark Höchst, Sanofi Deutschland GmbH, Bldg. G877, Room 421, 65926, Frankfurt am Main, Germany

    Dr. Jochen Maas

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    Dr. Roland Wesch & Dr. Dietmar Weitz

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    Jochen Maas

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Maas, J., Wesch, R., Weitz, D. (2013). Pharmacogenomics in Drug Metabolizing Enzymes and Transporters. In: Vogel, H.G., Maas, J., Hock, F.J., Mayer, D. (eds) Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-25240-2_47

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