Title

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

Authors

Onkar Singh
Ajay Mohan Mahajan, University of Akron, main campus
R. D. Ramasamy
C. Chuah
B. Chowbay

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 (C_0h, C_2h, 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 [C_0hrs (*10^-6 1/ml); 2.93; range: 1.7-4.61], 2hrs [C_2hrs (*10^-6 1/ml); 4.38; range: 1.49-6.88] and higher clearance at 0 hrs [CL_0hrs (*10^-2 L/hr/mg); 3.29; range: 1.88-6.14] compared to patients containing CC genotype [C_0hrs (*10^-6 1/ml); 4.23; range: 2.77-6.69; (p=0.002)], [C_2hrs (*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 [C_0hrs (*10^-6 1/ml); 5.39; range: 2.9-8.2; (p=0.002)], [C_2hrs (*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

Recommended Citation

Singh, Onkar; Mahajan, Ajay Mohan; Ramasamy, R. D.; Chuah, C.; and Chowbay, B., "Influence of SLC22A1 (hOCT1) Polymorphisms on Imatinib Mesylate Pharmacokinetics in Asian Patients with Chronic Myelogenous Leukemia" (2010). Mechanical Engineering Faculty Research. 497.
https://ideaexchange.uakron.edu/mechanical_ideas/497