title: Stereochemical determinants of the nature and consequences of drug metabolism.
abstract: Enantiomeric discrimination in drug disposition depends on the mechanism of the process under consideration. Absorption, distribution and excretion are generally passive processes which do not differentiate between enantiomers, but enzymic metabolism and protein binding, to plasma or tissue proteins, can show a high degree of stereoselectivity. In terms of metabolism, chiral discrimination occurs at both substrate and product levels, giving rise to five distinct stereochemical courses for drug metabolism, namely (i) prochiral-->chiral, (ii) chiral-->chiral, (iii) chiral-->diastereoisomer, (iv) chiral-->non-chiral and (v) chiral inversion. As a result, the metabolic and pharmacokinetic profiles of enantiomers after administration of racemic drugs can be very variable, so that the exposure to the two enantiomers may be very different. There now an enormous number of examples of each of these possibilities. The net result of the interaction of the stereoselectivities of these various processes can obscure the fact that one (or more) shows a marked stereoselectivity. This is particularly the case for metabolism: while the ratios of the total plasma clearance of the enantiomers of a wide range of drugs never exceed 2, individual metabolic pathways often show much greater stereoselectivity. This is particularly evident for those high-affinity, low-capacity enzyme systems which exhibit genetic polymorphism, namely the human cytochromes P450 2C18 and 2D6. This review provides an introduction to the stereoselectivity of drug metabolism.
authors.affiliation: Department of Pharmacology and Toxicology, St. Mary's Hospital Medical School, Imperial College of Science, Technology and Medicine, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Caldwell
mesh_terms: D000818:Animals; D006801:Humans; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D010597:Pharmacogenetics; D013237:Stereoisomerism
chemical_list: D004364:Pharmaceutical Preparations