Pharmacogenetics of SLCO1B1 gene and the impact of *1b and *15 haplotypes on irinotecan disposition in Asian cancer patients.
OBJECTIVE
To investigate the pharmacogenetic effect of SLCO1B1 *1a, *1b, *5 and *15 polymorphisms on irinotecan disposition in Asian cancer patients.


METHODS
Irinotecan was administered over 90 min either at 100 mg/m on days 1, 8 and 15 with the regimen being repeated every 28 days (N=28) or at 375 mg/m 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/m; 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/m; P=0.003) and 7-ethyl-10-hydroxycamptothecin (1.28+/-0.53 vs. 0.69+/-0.32 h/m; 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/m; P=0.016).


CONCLUSIONS
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.
Xiang
Xiaoqiang
X
Laboratory of Clinical Pharmacology, Division of Medical Sciences, National Cancer Centre, National University Hospital, Singapore.
Jada
Srinivasa Rao
SR
Li
Hui Hua
HH
Fan
Lu
L
Tham
Lai San
LS
Wong
Chiung Ing
CI
Lee
Soo Chin
SC
Lim
Robert
R
Zhou
Qing Yu
QY
Goh
Boon Cher
BC
Tan
Eng Huat
EH
Chowbay
Balram
B
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D001208:Asia / Q000453:epidemiology; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D005838:Genotype; D006207:Half-Life; D006239:Haplotypes / Q000502:physiology*; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D000077146:Irinotecan; D007958:Leukocyte Count / Q000706:statistics & numerical data; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008657:Metabolic Clearance Rate / Q000235:genetics; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000453:epidemiology*; D027361:Organic Anion Transporters / Q000235:genetics*
D000970:Antineoplastic Agents; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D000077146:Irinotecan; D002166:Camptothecin