Cytochrome P450 enzyme polymorphisms and adverse drug reactions Munir Pirmohamed *, B. Kevin Park Department of Pharmacology and Therapeutics, The University of Liverpool, Ashton Street, Liverpool L69 3GE, UK Abstract Adverse drug reactions (ADR) are common and many are thought to have a genetic predisposition. There has been a great deal of interest in the role of P450 enzyme gene polymorphisms in the pathogenesis of adverse reactions. The major impact to date of polymorphic P450 expression has been on pre-clinical drug development. However, the direct clinical impact of P450 polymorphisms on prediction of ADRs has been limited, largely because studies have been small and retrospective, and the literature shows an abundance of contradictory data. Furthermore, the clinical- and cost- effectiveness of pre-prescription genotyping for P450 polymorphisms has not been convincingly demonstrated. Further studies that address these deficiencies are urgently needed */only then will prospective P450 genotyping become routine in clinical practice. # 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Cytochrome P450; ADR; Polymorphism 1. Introduction An adverse drug reaction (ADR) can be defined as ‘‘an appreciably harmful or unpleasant reac- tion, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants preven- tion or specific treatment, or alteration of the dosage regimen, or withdrawal of the product’’ (Edwards and Aronson, 2000). ADRs are a major clinical problem accounting for a great deal of morbidity and mortality, and increased healthcare costs and pharmaceutical expenditure (Table 1). ADRs in general can be divided into two types (Pirmohamed et al., 1998): type A and type B. Type A (augmented) reactions are predictable from the known pharmacology of the drug and are usually an exaggeration of the known primary and/or secondary pharmacology of the drug. In contrast, type B (bizarre) ADRs are unpredictable from the known pharmacology of the drug, and show no apparent dose /response relationship. For both types of ADRs, there is evidence of genetic predisposition (Pirmohamed and Park, 2001). Since many of the drugs causing ADRs are metabolised by cytochrome P450 enzymes, the * Corresponding author. Tel.:  /44-151-794-5549; fax:  /44- 151-794-5540. E-mail address: munirp@liv.ac.uk (M. Pirmohamed). Toxicology xxx (2003) 1  /10 www.elsevier.com/locate/toxicol 0300-483X/03/$ - see front matter # 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/S0300-483X(03)00247-6 ARTICLE IN PRESS