Abstract
Individual variability in cytochrome P450 (P450) induction comprises an important component contributing to the difficulties in assessing and predicting metabolism-based drug-drug interactions in humans. In this article, we outline the major factors responsible for the individual variability in P450 induction, including variable transporter activity and metabolism of inducers in vivo, genetic variations of P450 genes and their regulatory regions, genetic variations of receptors and regulatory proteins required for induction, and different physiological and environmental elements. With a better understanding of the major determinants in P450 induction and a profile of the phenotypes of these determinants in each individual, it is believed that the individual variability in induction-mediated drug-drug interactions can be adequately evaluated.
Footnotes
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.104.003236.
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ABBREVIATIONS: P450, cytochrome P450; AhR, aryl hydrocarbon receptor; Arnt, Ah receptor nuclear translocator; CAR, constitutive androstane receptor; PXR, pregnane X receptor; RXR, retinoid X receptor; HNF4α, hepatocyte nuclear factor 4α; Pgp, P-glycoprotein; SNP, single nucleotide polymorphism; AUC, area under the curve; OATP-C, organic anion-transporting polypeptide C; PM, poor metabolizer; EM, extensive metabolizer; PB, phenobarbital; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; h, human; DBD, DNA binding domain; LBD, ligand binding domain; DDE, 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene.
- Received December 6, 2004.
- Accepted January 21, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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