Analytical and Bioanalytical Chemistry

, Volume 392, Issue 6, pp 1093–1108

Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation

  • Ulrich M. Zanger
  • Miia Turpeinen
  • Kathrin Klein
  • Matthias Schwab
Review

DOI: 10.1007/s00216-008-2291-6

Cite this article as:
Zanger, U.M., Turpeinen, M., Klein, K. et al. Anal Bioanal Chem (2008) 392: 1093. doi:10.1007/s00216-008-2291-6

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.

Keywords

Drug metabolismFunctional genomicsGenotypeMutationPharmacogeneticsPhenotypeSingle-nucleotide polymorphism

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

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Ulrich M. Zanger
    • 1
    • 2
  • Miia Turpeinen
    • 1
    • 2
    • 3
  • Kathrin Klein
    • 1
    • 2
  • Matthias Schwab
    • 1
    • 2
  1. 1.Dr. Margarete Fischer-Bosch Institute of Clinical PharmacologyStuttgartGermany
  2. 2.Department of Clinical PharmacologyUniversity of TuebingenTuebingenGermany
  3. 3.Department of Pharmacology and ToxicologyUniversity of OuluOuluFinland