Role of Human Organic Cation Transporter 1 (hOCT1) Polymorphisms in Lamivudine (3TC) Uptake and Drug-Drug Interactions

Abstract

Lamivudine (3TC), a drug used in the treatment of HIV infection, needs to cross the plasma membrane to exert its therapeutic action. Human Organic cation transporter 1 (hOCT1), encoded by the SLC22A1 gene, is the transporter responsible for its uptake into target cells. As SLC22A1 is a highly polymorphic gene, the aim of this study was to determine how SNPs in the OCT1-encoding gene affected 3TC internalization and its interaction with other co-administered drugs. HEK293 cells stably transfected with either the wild type form or the polymorphic variants of hOCT1 were used to perform kinetic and drug-drug interaction studies. Protein co-immunoprecipitation was used to assess the impact of selected polymorphic cysteines on the oligomerization of the transporter. Results showed that 3TC transport efficiency was reduced in all polymorphic variants tested (R61C, C88R, S189L, M420del, and G465R). This was not caused by lack of oligomerization in case of variants located at the transporter extracellular loop (R61C and C88R). Drug-drug interaction measurements showed that co-administered drugs [abacavir (ABC), zidovudine (AZT), emtricitabine (FTC), tenofovir diproxil fumarate (TDF), efavirenz (EFV) and raltegravir (RAL)], differently inhibited 3TC uptake depending upon the polymorphic variant analyzed. These data highlight the need for accurate analysis of drug transporter polymorphic variants of clinical relevance, because polymorphisms can impact on substrate (3TC) translocation but even more importantly they can differentially affect drug-drug interactions at the transporter level.

Ligand-dependent modulation of hOCT1 transport reveals discrete ligand binding sites within the substrate translocation channel

“…To understand the structural implications of multiple ligand modulation of hOCT1 transport activity, we used our constructed hOCT1 homology model as a template to dock several of the drugs that demonstrated significant differences in the CCF assay. It should be noted that both the large extracellular and small intracellular loop were omitted from our model for simplicity sake, despite some reports [40, 41] indicating that these regions may be important in the initial step in ligand recognition. Most compounds tested in the CCF assay (MPP + , serotonin, TEA, metformin, BSP, acyclovir, ritonavir, lamivudine, cimetidine, famotidine, imatinib, fluoxetine, lamotrigine, thiamine, prostaglandin E2, quercetin, berberine, and ethidium) were docked into the homology model using UCSF DOCK 6.7 (ranitidine was not docked due to issues with improper ligand parameterization).…”

Sorafenib Resistance in Hepatocellular Carcinoma: The Relevance of Genetic Heterogeneity

“…Several OCT1 variants (R61C, C88R, S189L, M420del, and G465R) were shown to reduce the translocation efficiency of lamivudine, an antiviral drug, and affected drug-drug interaction [60]. In contrast, variants such as S29L, C88R, E284K, G465R, R61C, and R206C show reduction/loss of the transport activity of OCT1 to its substrates and, hence, could be valuable in improving drug uptake activity [52,61].…”

Drug-Drug Interactions at Organic Cation Transporter 1

“…The concomitant administration of lamivudine and these potent OCT inhibitors is common in the regimen of highly active antiretroviral therapy (HAART). The DDIs may be of great significance in clinical practice, particularly for the pharmacokinetics, of lamivudine ( Zhang et al, 2000 ; Jung et al, 2008 ; Minuesa et al, 2009 ; Jung et al, 2013 ; Arimany-Nardi et al, 2016 ). Consistently, Jung et al documented that the addition of OCT1 and OCT2 inhibitors such as ritonavir and nelfinavir could reduce the accumulation of lamivudine in the CD4 cells of HIV-infected patients ( Jung et al, 2013 ).…”