Association of genetic polymorphisms in the influx transporter SLCO1B3 and the efflux transporter ABCB1 with imatinib pharmacokinetics in patients with chronic myeloid leukemia
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This study explored the association of 14 single nucleotide polymorphisms (SNPs) in 3 genes coding for influx transporters (SLC22A1, SLCO1B1, andSLCO1B3), 2 genes coding for efflux transporters (ABCB1 and ABCG2), and 4 genes coding for enzymes (CYP2C9, CYP2C19, CYP2D6, and CYP3A5) with the pharmacokinetics of imatinib in Japanese patients with chronic myeloid leukemia (CML). Pharmacokinetic parameters were estimated by a population pharmacokinetic analysis based on 622 plasma samples from 34 patients at steady-state. Approximately 4.6-fold variability in individual clearance was observed (range, 3.4-15.5 L/hr). The individual estimated clearance was significantly increased in patients with SLCO1B3 334GG genotype (median value ± SD, 9.5 ± 3.1 L/hr; n = 19) compared with SLCO1B3 334TT and TG genotypes (7.0 ± 3.1 L/hr; n = 15) (P = 0.019). Patients with ABCB1 3435CC genotype had significantly higher imatinib clearance (12.7 ± 3.0 L/hr; n = 7) compared with patients with ABCB1 3435CT and TT genotypes (7.9 ± 2.7 L/hr; n= 27) (P = 0.035). In conclusion, the present study suggests that SNPs of the influx transporter SLCO1B3 and the efflux transporter ABCB1 were functionally associated with individual variability of imatinib pharmacokinetics in Japanese patients with CML.
- Therapeutic Drug Monitoring
Therapeutic Drug Monitoring 33(2), 244-250, 2011-04-01
Lippincott Williams & Wilkins