Received for publication February 5, 2008.
Revised May 15, 2008.
Accepted for publication May 15, 2008.

Relevance of the organic cation transporters 1 and 2 for antiretroviral therapy in HIV infection

Abstract

Carrier-mediated transport across cell membranes is an important determinant of activity, resistance and toxicity of chemotherapeutic agents including antiretroviral drugs (ARDs). The organic cation transporters OCT1 and OCT2 have been implicated in the translocation of different cationic drugs, but so far were insufficiently tested for interactions with ARDs. Here, we assessed among cationic drugs commonly used in HIV therapy inhibitors and substrates of OCTs, and analyzed the tissue distribution of OCTs and their expression in lymph nodes, the primary intracellular target of HIV and ARDs. Inhibitors were identified by measuring the attenuated uptake of the radiolabeled model substrate 1-methyl-4-phenylpyridinium into OCT-transfected HEK-293-cells in the presence of ARDs. Substrates were identified by measuring OCT-specific intracellular accumulation using LC-MS/MS. Inhibitory drugs were (in order of increasing potency): nelfinavir < ritonavir < saquinavir < indinavir < trimethoprim < pentamidine, with consistently lower IC₅₀ values determined for OCT1. Substrates with highest transport efficacy (v_max/K_M) were lamivudine (OCT1: 8 µl/mg protein/min, OCT2: 4.4 µl/mg protein/min) and zalcitabine (OCT1: 4.1 µl/mg protein/min, OCT2: : 2.6 µl/mg protein/min ). Using quantitative real-time PCR, a marked expression level of OCT1 was detected in human samples of liver, ovary, prostate and testis, and of OCT2 in kidney, colon, heart, skeletal muscle and testis. Expression of OCTs in lymph nodes was low in HIV-negative control individuals, but dramatically increased in HIV-infected persons. These data suggest that drug interactions about the OCTs may be relevant for the antiretroviral therapy, in particular by influencing drug accession to infected tissues and hepatic or renal elimination.

Key words: antivirals, clinical pharmacology, drug transport, drug-drug interactions, organic cation transport, transporters