The c.480C>G polymorphism of hOCT1 influences imatinib clearance in patients affected by chronic myeloid leukemia

Abstract

The aim of the study was to investigate any possible influence of polymorphisms of transmembrane transporters human organic cation transporter 1 (hOCT1), ABCB1, ABCG2 on imatinib pharmacokinetics in 33 men and 27 women (median age and range, 56 and 27-79 years, respectively) affected by chronic myeloid leukemia. A population pharmacokinetic analysis was performed to investigate imatinib disposition in every patient and the role of transporter polymorphisms. Results showed that the α1-acid glycoprotein and the c.480C>G genotype of hOCT1 had a significant effect on apparent drug clearance (CL/F) being responsible, respectively, for a 20% and 10% decrease in interindividual variability (IIV) of CL/F (from 50.1 up to 19.6%). Interestingly, 25 patients carrying at least one polymorphic c.480 G allele had a significant lower CL/F value with respect to the 35 c.480CC individuals (mean±s.d., 9.6±1.6 vs 12.1±2.3 l h(-1), respectively; P<0.001). In conclusion, the hOCT1 c.480C>G SNP may significantly influence imatinib pharmacokinetics, supporting further analyses in larger groups of patients.

Polycomb Genes are Associated with Response to Imatinib in Chronic Myeloid Leukemia

“…When we analyzed the c.480 C>G hOCT1 polymorphism, we found that the wild-type CC genotype had a favorable impact on 36 months-EFS (87.5 vs 30% of individuals carrying the G allele; p = 0.04), hence confirming our previous results in this subset of patients [7]. In our series, 50% of cases showed a wild-type genotype.…”

“…The same analyses were performed in combination with hOCT1 genotyping, because our previous work demonstrated that the hOCT1 c.480C>G polymorphism significantly influences both drug disposition and event-free survival (EFS) [7]. Therefore, the inclusion of these variables within the analysis could improve the identification of possible markers of clinical outcome.…”

“…For this reason, several groups have investigated the role of genetic variants in predicting CML patients' response to imatinib [6]. We have recently associated transmembrane transporter hOCT1 germline variants with imatinib pharmacokinetics and therapeutic activity [7]. Despite these promising results, no genetic factor has been conclusively linked to the clinical efficacy of imatinib.…”

Imatinib-induced ophthalmological side-effects in GIST patients are associated with the variations of EGFR, SLC22A1, SLC22A5 and ABCB1

“…Our results indicated that GG+CG genotypes may be correlated with increased cellular exposure and increase risk of toxicities of Imatinib. 37 OCTN2 (SLC22A5) is another member of the SLC22 family of plasma membrane solute carrier proteins. 38 OCTN2 is expressed ubiquitously, with high expression in kidneys and lower expression in heart, skeletal muscles, and other tissues.…”

Methods: for studying pharmacogenetic profiles of combination chemotherapeutic drugs

“…For example, patients carrying a low-activity allele for uridine diphosphate glucuronosyl transferase may tolerate CPT-11 when the infusion rate is very low [68], despite this is not considered a standard regimen. Therefore, it is likely that the evaluation of drug concentrations (an endophenotype) in mathematical models may help in deciphering interindividual variability [35,69].…”