Abstract
We investigated the elimination routes for the 200 drugs that are sold most often by prescription count in the United States. The majority (78%) of the hepatically cleared drugs were found to be subject to oxidative metabolism via cytochromes P450 of the families 1, 2 and 3, with major contributions from CYP3A4/5 (37% of drugs) followed by CYP2C9 (17%), CYP2D6 (15%), CYP2C19 (10%), CYP1A2 (9%), CYP2C8 (6%), and CYP2B6 (4%). Clinically well-established polymorphic CYPs (i.e., CYP2C9, CYP2C19, and CYP2D6) were involved in the metabolism of approximately half of those drugs, including (in particular) NSAIDs metabolized mainly by CYP2C9, proton-pump inhibitors metabolized by CYP2C19, and beta blockers and several antipsychotics and antidepressants metabolized by CYP2D6. In this review, we provide an up-to-date summary of the functional polymorphisms and aspects of the functional genomics of the major human drug-metabolizing cytochrome P450s, as well as their clinical significance.
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Abbreviations
- ADME:
-
Absorption, distribution, metabolism, excretion
- CAR:
-
Constitutive androstane receptor
- CYP:
-
Cytochrome P450
- MALDI-TOF:
-
Matrix-assisted laser desorption ionisation-time of flight
- NNRTI:
-
Non-nucleosidic reverse transcriptase inhibitor
- NSAID:
-
Nonsteroidal antiinflammatory drug
- PD:
-
Pharmacodynamics
- PK:
-
Pharmacokinetics
- PPI:
-
Proton pump inhibitor
- PXR:
-
Pregnane X receptor
- XREM:
-
Xenobiotic-responsive enhancer module
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Supported by the Robert-Bosch Foundation, Stuttgart, and by the Academy of Finland (to MT).
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Zanger, U.M., Turpeinen, M., Klein, K. et al. Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation. Anal Bioanal Chem 392, 1093–1108 (2008). https://doi.org/10.1007/s00216-008-2291-6
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DOI: https://doi.org/10.1007/s00216-008-2291-6