1. ¹Product Lifecycle Management Department, Daiichi, Tokyo, Japan
2. ²Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Gunma, Japan
3. ³PMS and Product Information Management Department, Daiichi, Tokyo, Japan
4. ⁴Drug Safety Research Laboratory, R&D Division, Daiichi, Tokyo, Japan
5. ⁵Drug Metabolism and Physicochemistry Research Laboratory, R&D Division, Daiichi, Tokyo, Japan

Correspondence: K Hirata, Product Lifecycle Management Department, Daiichi Pharmaceutical Co, Ltd, 1-8 Nihonbashi-Koamicho, Chuo-ku, Tokyo 103-8541, Japan. E-mail: hiratyl9@daiichipharm.co.jp

Received 30 August 2006; Revised 1 January 2007; Accepted 1 January 2007; Published online 6 March 2007.

Abstract

Genetic risk factors for ticlopidine-induced hepatotoxicity were determined in 22 Japanese patients with ticlopidine-induced hepatotoxicity and 85 Japanese patients who tolerated ticlopidine therapy without experiencing adverse reactions. There was a significant correlation between ticlopidine-induced hepatotoxicity and five human leukocyte antigen (HLA) alleles: HLA-A^*3303, HLA-B^*4403, HLA-Cw^*1403, HLA-DRB1^*1302 and HLA-DQB1^*0604 (corrected probability (P)-value (Pc)<0.01). In particular HLA-A^*3303 was present in 15 (68%) of the 22 patients with ticlopidine-induced hepatotoxicity and in 12 (14%) of the 85 ticlopidine-tolerant patients (odds ratio, 13.04; 95% confidence interval (CI), 4.40–38.59; the corrected P-value (Pc)=1.24 10^–5). HLA-A^*3303 was present in 12 (86%) of the 14 patients with ticlopidine-induced cholestatic hepatotoxicity (odds ratio, 36.50; 95% CI, 7.25–183.82, Pc=7.32 10^–7). Ticlopidine-induced severe cholestatic hepatotoxicity occurred more frequently in subjects with HLA-A^*3303 and its haplotype in Japanese patients. These findings may explain the high incidence of ticlopidine-induced hepatotoxicity in Japanese patients mediated via an immune-mediated mechanism.