Interaction of Imatinib with Human Organic Ion Carriers

Abstract

Purpose: The activity of imatinib in leukemia has recently been linked with expression of the organic cation transporter 1 (OCT1) gene SLC22A1. Here, we characterized the contribution of solute carriers to imatinib transport in an effort to further understand mechanisms involved in the intracellular uptake and retention (IUR) of the drug. Experimental Design: IUR of [ 3 H]imatinib was studied in Xenopus laevis oocytes and HEK293 cells expressing OATP1A2, OATP1B1, OATP1B3, OCT1-3, OCTN1-2, or OAT1-3. Gene expression was determined in nine leukemia cell lines using the Affymetrix U133 array. Results: Imatinib was not found to be a substrate for OCT1 in oocytes (P = 0.21), whereas in HEK293 cells IUR was increased by only 1.20-fold relative to control cells (P = 0.002). Furthermore, in 74 cancer patients, the oral clearance of imatinib was not significantly altered in individuals carrying reduced-function variants in SLC22A1 (P = 0.99). Microarray analysis indicated that SLC22A1 was interrelated with gene expression of various transporters, including ABCB1, ABCC4, ABCG2 (negative), and OATP1A2 (positive). Imatinib was confirmed to be a substrate for the three efflux transporters (P < 0.05) as well as for OATP1A2 (P = 0.0001).Conclusions:This study suggests that SLC22A1 expression is a composite surrogate for expression of various transporters relevant to imatinib IUR. This observation provides a mechanistic explanation for previous studies that have linked SLC22A1 with the antitumor activity of imatinib. Because of its high expression in the intestine, ciliary body, gliomas, and leukemia cells, OATP1A2 may play a key role in imatinib pharmacokinetics-pharmacodynamics.

Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia

“…24 In the human intestine, OATP1A2 is expressed on the apical brush-border membrane of human enterocytes, 45 which suggests that net absorption of IM may reflect a situation in which there is greater uptake by SLCO1A2 (OATP1A2) than efflux by ABCG2 (BCRP). In this study, SLCO1A2 genotyping was not performed because SNPs that affect OATP1A2 transport activity are not typically found in the Asian population.…”

“…[19][20][21] Although IM is a substrate of OCT1, 15,22,23 no association between IM and SLC22A1 286C4T or 1498G4A, variants not common in the Japanese population, was previously observed. 24,25 In addition, in vitro studies have shown that organic anion-transporting polypeptide 1B3 (OATP1B3), which is encoded by SLCO1B3, contributes to IM uptake into hepatocytes. 24 However, to date, the influence of SLCO1B3 SNPs on the pharmacokinetics of IM has not been reported.…”

“…24,25 In addition, in vitro studies have shown that organic anion-transporting polypeptide 1B3 (OATP1B3), which is encoded by SLCO1B3, contributes to IM uptake into hepatocytes. 24 However, to date, the influence of SLCO1B3 SNPs on the pharmacokinetics of IM has not been reported.…”

Lysosomal Sequestration Determines Intracellular Imatinib Levels

“…The putative clinical significance of potential imatinib uptake transporters has extensively been investigated in the last decade as reflected by the numerous (pre-) clinical studies that have been conducted to investigate their role in the pharmacokinetics and/or pharmacodynamics of imatinib (Thomas et al, 2004;Crossman et al, 2005;White et al, 2006White et al, , 2007White et al, , 2010Hu et al, 2008;Wang et al, 2008;White and Hughes, 2012;Nies et al, 2014). SLC22A1, also referred to as organic cation transporter (OCT) 1, has frequently been implicated in the intracellular uptake and disposition of imatinib in CML cells (Thomas et al, 2004;White et al, 2006), although controversy exists with regard to its precise role (Burger et al, 2013;Nies et al, 2014).…”

285 Downregulation of Organic Cation Transporters Oct1 (Slc22a1) and Oct3 (Slc22a3) in Human Hepatocellular Carcinoma and Their Prognostic Significance

“…They are held responsible for the cytotoxicity of platin derivatives and are predictors of responses to small molecules [11,[22][23][24]. Downregulation in HCC could be responsible for a worse or lacking response towards platin treatment.…”