1. ¹Clinical Pharmacology and Discovery Medicine, GlaxoSmithKline, Philadelphia, PA, USA
2. ²Etiologics Ltd., Medical Research Council, Harwell, Oxfordshire, UK
3. ³Discovery Genetics, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, UK
4. ⁴Genetics Research, GlaxoSmithKline, Research Triangle Park, NC, USA

Correspondence: C-F Xu, Discovery Genetics, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK. Tel: +44 1438 76 8392; Fax: +44 1438 76 4231; E-mail: cfx74267@gsk.com

Received 31 July 2003; Revised 26 September 2003; Accepted 2 October 2003; Published online 2 December 2003.

Abstract

Tranilast (N-(3'4'-demethoxycinnamoyl)-anthranilic acid (N-5)) is an investigational drug for the prevention of restenosis following percutaneous transluminal coronary revascularization. An increase in bilirubin levels was observed in 12% of patients upon administration of tranilast in a phase III clinical trial. To identify the potential genetic factors that may account for the drug-induced hyperbilirubinemia, we examined polymorphisms in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene in over a thousand patients. Our results suggested that the TA repeat polymorphism in UGT1A1, which predisposes some individuals to Gilbert's syndrome, predicted the susceptibility to tranilast-induced hyperbilirubinemia. The (TA)₇/(TA)₇ genotype was present in 39% of the 127 hyperbilirubinemic patients vs 7% of the 909 controls (P=2 10^-22). Rapid identification of genetic factors accounting for the observed adverse effect during the course of a double-blind clinical trial demonstrated the potential application of pharmacogenetics in the clinical development of safe and effective medicines.