Deficient Metabolism Leading to Dose Dependent Toxicity

The best example is the association of CYP2C9 polymorphisms with warfarin dose requirements and the risk of bleeding. Warfarin is widely used, perhaps the most common indication being the prevention of embolic complications in patients with atrial fibrillation. The major risk of warfarin treatment is hemorrhage; the incidence varies from 10 to 24 episodes per 100 patients for all bleeding complications and from 1.2 to 7.0 episodes per 100 patients for major bleeding complications (37). The risk of bleeding increases with the intensity of anticoagulation. Furthermore, there is about 10- to 50-fold interindividual variability in the dosage requirements necessary to maintain the international normalized ratio (INR) within a target range (most commonly between 2 and 3). Warfarin is administered as a racemate, with S-warfarin being three times more potent than R-warfarin (38,39). S-warfarin is metabolized by the P450 isoform CYP2C9; allelic variants of this isoform with reduced catalytic activity (between 5% and 12% of the activity of wild-type alleles), and in some cases, altered substrate specificity have been identified (40). Both the variants CYP2C9*2 and CYP2C9*3 show decreased clearance of warfarin in vitro and in vivo (compared with the wild-type CYP2C9*1). In accordance with this, individuals with these allelic variants require low doses of warfarin to achieve anticoagulation (41 -44). Control of warfarin therapy on commencement is also more difficult in these patients, and they are also more liable to bleed while on warfarin (41). Despite the consistent data on the effect of CYP2C9 allelic variants on warfarin dosage and the risk of hemorrhage, it may be premature to advise routine pre-prescription genotyping for three main reasons. First, a great deal of interindividual variability exists even within the same genotype group (45), such that the predictive accuracy of CYP2C9 genotyping is likely to be too low to make it clinically useful. Second, polymorphisms in other genes in the warfarin pathway may also be important determinants in dosage, and their inclusion may improve the predictability of dose requirement. The utility of this has recently been shown by study of the vitamin K epoxide reductase gene (VKORC1), the target for the action of warfarin, which acts as a major determinant of daily warfarin dose requirements (46). Third, the interaction between these polymorphisms and environmental factors such as vitamin K intake has not been adequately defined. The importance of considering both genetic and environmental factors in determining daily warfarin dose requirements has recently been demonstrated by Sconce et al. (47). They were able to show that by combining age, height and CYP2C9 (*2 and *3) and the VKORC1 (—1639G > A) single nucleotide polymorphisms, 55% of the variance in warfarin dose requirements could be accounted for.

Similar considerations also apply to Phase II enzymes. For example, slow acety-lation has been associated with a number of adverse effects, including vomiting with sulfasalazine (48), peripheral neuropathy with isoniazid (49,50), and SLE with procainamide (51). More recently, a large number of functionally relevant polymorphisms have been identified in the various glucuronosyl transferase isoforms (52). A pharmacogenetic study of 12 candidate genes in patients who had developed hepatotoxicity with the anti-Parkinsonian drug tolcapone (53) showed an association only with the Ala181 and Ser184 variants in the UGT1A gene complex. This is in accordance with the fact that glucuronidation is the main metabolic route of tolcapone elimination. However, it is important to note that the authors used an elevation in transaminase levels of 1.5 times the upper limit of normal as a definition of hepatotoxicity, which may inadvertently have included some elderly patients who did not have true tolcapone-mediated liver damage. Perhaps, more convincing is the association between UGT1A polymorphisms and haplotypes and the risk of toxicity (including neutropenia) with irinotecan, an anticancer agent used in bowel cancer (54). More recently, a striking association was shown between tranilast-induced hyperbilirubnemia and the UGT1A1 promoter region polymorphism. Tranilast, a drug designed to prevent restenosis following coronary angioplasty, leads to increased bilirubin levels in 12% of the patients. The TA7/TA7 genotype in UGT1A1, which predisposes some individuals to Gilbert's syndrome, was present in 39% of the 127 hyperbilirubinemia patients, compared with 7% of the 909 controls (P = 2 x 10" 22) (55,56). The mechanism of this association however remains unclear.

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