Transport of Lamivudine [(-)-β-l-2′,3′-Dideoxy-3′-thiacytidine] and High-Affinity Interaction of Nucleoside Reverse Transcriptase Inhibitors with Human Organic Cation Transporters 1, 2, and 3

Abstract

Nucleoside reverse transcriptase inhibitors (NRTIs) need to enter cells to act against the HIV-1. Human organic cation transporters (hOCT1-3) are expressed and active in CD4ϩ T cells, the main target of HIV-1, and have been associated with antiviral uptake in different tissues. In this study, we examined whether NRTIs interact and are substrates of hOCT in cells stably expressing these transporters. Using min). In drug-drug interaction experiments, we analyzed cis-inhibition of [3 H]3TC uptake by ABC and AZT and found that 40 to 50% was inhibited at low concentrations of the drugs (K i ϭ 22-500 pM). These data reveal that NRTIs experience a high-affinity interaction with hOCTs, suggesting a putative role for these drugs as modulators of hOCT activity. Finally, 3TC is a novel substrate for hOCTs and the inhibition of its uptake at low concentrations of ABC and AZT could have implications for the pharmacokinetics of 3TC.

Expression of Organic Cation Transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) Is Affected by Genetic Factors and Cholestasis in Human Liver†

“…The rs3088442 variant is in complete linkage to the intronic OCT3 variant rs2048327 and, of note, in a genome-wide association study investigating susceptibility for coronary artery disease, 54 this variant was recently identified. Thus, in addition to a potential clinical relevance of OCT3 for drug response (such as efficacy of oxaliplatin chemotherapy, 55 lamivudine as drug substrate 19,20 ) OCT3 (SLC22A3) may contribute also as a susceptibility factor for development of certain diseases such as coronary artery disease 54 but also other diseases (such as obsessive-compulsive disorder 37 ).…”

“…OCT1 substrates include antiviral drugs [18][19][20] and the antidiabetic drug metformin. 21 The anticancer drug oxaliplatin, 22,23 the histamine H 2 receptor antagonist cimetidine, 24,25 and the antiviral drug lamivudine 19,20 are substrates for both OCT1 and OCT3. Notably, hepatocytes are the pharmacological target cells of lamivudine, when it is used to treat chronic hepatitis B, 26 and of metformin.…”

Organic Cation Transporter 2 Overexpression May Confer an Increased Risk of Gentamicin-Induced Nephrotoxicity

“…The structural complexity of the OCT binding pocket is known, and for several substrates, including choline, tetraethylammonium (TEA), and 1-methyl-4-phenylpyridinium (MPP), two binding sites have been described, but no cooperativity was reported (48)(49)(50). Substrate-dependent inhibitory ligand interaction is a common characteristic for OCT2 (50).…”

Evaluation and Prediction of Potential Drug-Drug Interactions of Linagliptin Using In Vitro Cell Culture Methods

“…Therefore, although it has not yet been tested in a clinical situation, sitagliptin exposure may be increased by interactions with other drugs such as ibuprofen, fenofibric acid, and probenecid by blocking the SLC transporter OAT3 (Chu et al, 2007). Members of the OCT family of transporters appear to have two binding sites (Minuesa et al, 2009). In our experiments, linagliptin demonstrated differential ability to inhibit the transport of three different substrates, MPP + , metformin, and TEA, in cells expressing either OCT1 or OCT2.…”