Mechanical Engineering Faculty Research

Title

Influence of SLC22A1 (hOCT1) Polymorphisms on Imatinib Mesylate Pharmacokinetics in Asian Patients with Chronic Myelogenous Leukemia

Document Type

Article

Publication Date

5-20-2010

Abstract

This study aimed to explore the influence of SLC22A1 IVS2+797C>G (rs4646274) polymorphism on the pharmacokinetics of imatinib mesylate (IM) in Asian patients with chronic myelogenous leukemia (CML). Methods: A total of 37 patients were enrolled in a prospective pharmacogenetic study conducted in patients with CML, all receiving IM median dose 400 mg/day (range: 300-800 mg/day). The median age and weight of patients were 49 years (range: 24-71 years) and 68 kg (range: 47-135.5 kg) respectively. The majority of the patients were Chinese (86.5%) followed by Malays (10.8%) and Indians (2.7%). IM pharmacokinetics (C0h, C2h, and CL) were determined in the CML patients. SLC22A1 polymorphism IVS2+797C>G (rs4646274) was determined in all patients. The nonparametric Mann-Whitney U test and Kruskal-Wallis test were used to find the association between rs4646274 genotype status and IM pharmacokinetics in the CML patients. Results: The genotype frequencies of rs4646274 SNP were CC (37.8%); CG (40.5%) and GG (21.7%). Patients carrying the IVS2+797CG genotype had significantly lower median concentration of IM at 0hrs [C0hrs (*10-6 1/ml); 2.93; range: 1.7-4.61], 2hrs [C2hrs (*10-6 1/ml); 4.38; range: 1.49-6.88] and higher clearance at 0 hrs [CL0hrs (*10-2 L/hr/mg); 3.29; range: 1.88-6.14] compared to patients containing CC genotype [C0hrs (*10-6 1/ml); 4.23; range: 2.77-6.69; (p=0.002)], [C2hrs (*10-6 1/ml); 5.78; range: 2.07-9.61; (p=0.01)] and [CL (*10-2 L/hr/mg); 2.07; range: 1.26-3.76; (p=0.018), respectively] and patients with GG genotypes [C0hrs (*10-6 1/ml); 5.39; range: 2.9-8.2; (p=0.002)], [C2hrs (*10-6 1/ml); 7.68; range: 4.16-12.9; (p=0.004)] and [CL (*10-2 L/hr/mg); 1.96; range: 0.95-3.59; (p=0.02), respectively]. No significant differences were found between genotype CC and GG for IM pharmacokinetics. Of the 35 patients in whom data on BCR-ABL transcript levels were available, 5 were in complete molecular remission and 21 were in major molecular remission. Conclusions: This exploratory study suggests that SLC22A1 IVS2+797C>G polymorphism may influence the pharmacokinetics of IM in CML patients. Future validation in a larger sample size is ongoing.

ASCO Annual Meeting Proceedings

Publication Title

ASCO Annual Meeting Proceedings

Volume

28

Issue

15

First Page

e13594