RT Journal Article
SR Electronic
T1 Relevance of the Organic Cation Transporters 1 and 2 for Antiretroviral Drug Therapy in Human Immunodeficiency Virus Infection
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1616
OP 1623
DO 10.1124/dmd.108.020826
VO 36
IS 8
A1 Norma Jung
A1 Clara Lehmann
A1 Andrea Rubbert
A1 Meike Knispel
A1 Pia Hartmann
A1 Jan van Lunzen
A1 Hans-Juergen Stellbrink
A1 Gerd Faetkenheuer
A1 Dirk Taubert
YR 2008
UL http://dmd.aspetjournals.org/content/36/8/1616.abstract
AB Carrier-mediated transport across cell membranes is an important determinant of activity, resistance, and toxicity of chemotherapeutic agents including antiretroviral (ARV) drugs (ARDs). The organic cation transporters (OCTs) 1 and 2 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 human immunodeficiency virus (HIV) therapy inhibitors and substrates of OCTs, and analyzed the tissue distribution of OCTs and their expression in lymph nodes (LNs), 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 human embryonic kidney-293 cells in the presence of ARDs. Substrates were identified by measuring OCT-specific intracellular accumulation using liquid chromatography/tandem mass spectrometry. 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 (Vmax/Km) 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 polymerase chain reaction, 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 LNs 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 ARV therapy, in particular by influencing drug accession to infected tissues and hepatic or renal elimination. The American Society for Pharmacology and Experimental Therapeutics