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Evolution of drug metabolism: Hitchhiking the technology bandwagon
Author(s) -
Miners John O
Publication year - 2002
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1046/j.1440-1681.2002.03768.x
Subject(s) - in silico , computational biology , functional genomics , cytochrome p450 , drug metabolism , biology , adme , drug discovery , in vivo , gene isoform , homology modeling , biochemistry , drug , pharmacology , enzyme , gene , genetics , genomics , genome
Summary 1. The application of a range of established and emerging technologies and experimental approaches has allowed investigation of cytochrome P450 (CYP) and uridine diphosphate‐glucuronosyltransferase (UGT) at the functional, structural and molecular levels to address questions of therapeutic relevance, particularly the wide interindividual variability in metabolic clearance characteristic of drugs and chemicals metabolized by these enzymes. 2. Studies in vivo initially identified the various factors that contribute to interindividual variability. Subsequently, human liver microsomal kinetic approaches, together with the cloning and functional characterization of recombinant CYP and UGT isoforms, led to the development of in vitro strategies that allowed the qualitative prediction of those factors likely to alter the metabolic clearance of a given compound in vivo . More recently, computer ( in silico ) modelling has been used to complement the laboratory based procedures. 3. The application of molecular biological approaches additionally allowed identification of the mutations responsible for CYP and UGT genetic polymorphism and, in some instances, the domains and individual amino acids that confer isoform substrate and inhibitor selectivities. Homology models, developed using X‐ray crystallographic data as the template, potentially enable prediction of the functional consequences of altered CYP structure. 4. The rapid advances occurring in genomics, proteomics, gene expression analysis and computer modelling will allow further unravelling of the complexities of drug metabolism and improved prospects for the individualization of drug therapy.