Pharmacogenetics of SLCO1B1 gene and the impact of *1b and *15 haplotypes on irinotecan disposition in Asian cancer patients

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Abstract
Objective To investigate the pharmacogenetic effect of SLCO1B1 *1a, *1b, *5 and *15 polymorphisms on irinotecan disposition in Asian cancer patients. Experimental design Irinotecan was administered over 90 min either at 100 mg/m2 on days 1, 8 and 15 with the regimen being repeated every 28 days (N=28) or at 375 mg/m2 once every three weeks (N=43). Plasma concentrations of irinotecan, 7-ethyl-10-hydroxycamptothecin and 7-ethyl-10-hydroxycamptothecinG were analysed after the first dose of the first cycle and the influence of SLCO1B1 *1a, *1b, *5 and *15 polymorphisms on the disposition of irinotecan and its metabolites were evaluated. Results Pharmacokinetic parameters were obtained from 71 cancer patients. Genotypic–phenotypic correlates showed the clearance of irinotecan to be 3-fold lower in patients carrying the *15 haplotype than cancer patients with the reference genotype *1a/*1a (9.57±3.15 vs. 28.86±10.97 l/h/m2; P=0.001). The area under the plasma concentration–time curve from zero to infinity and normalized by dose and body surface area (AUC0–nf/dose/BSA) were significantly higher in patients harbouring the *15 haplotype than patients with the reference genotype for irinotecan (39.27±15.17 vs. 17.32±6.30 h/m5; P=0.003) and 7-ethyl-10-hydroxycamptothecin (1.28±0.53 vs. 0.69±0.32 h/m5; P=0.021). The exposure levels to 7-ethyl-10-hydroxycamptothecinG also showed a statistically significant trend among the SLCO1B1 haplotype pairs, being approximately 10-fold lower in patients with *15 haplotype than with patients harbouring the reference genotype (3.57±1.95 vs. 12.0±6.09 h/m5; P=0.016). Conclusion These findings suggest that (1) SLCO1B1 haplotypes may have a significant influence on the disposition of irinotecan and its metabolites in Asian cancer patients, and (2) patients with SLCO1B1*15 haplotype may be susceptible to increased sensitivity to irinotecan, which may manifest itself either by increased efficacy or toxicity or both owing to the increased exposure levels to 7-ethyl-10-hydroxycamptothecin.