Abstract
Recently, we cloned a human organic cation transporter, hOCT1, which is expressed primarily in the liver. hOCT1 plays an important role in the cellular uptake and elimination of various xenobiotics including therapeutically important drugs. HIV protease inhibitors are a new class of therapeutic agents. The purpose of this study was to elucidate the interactions of HIV protease inhibitors with hOCT1 and to determine whether hOCT1 is involved in the elimination of these compounds. We studied the interactions of HIV protease inhibitors with hOCT1 in a transiently transfected human cell line, HeLa. Uptake studies were carried out 40 h post-transfection using the radiolabeled model organic cation, [14C]tetraethylammonium (TEA), under different experimental conditions. In cis-inhibition studies, all of the HIV protease inhibitors tested, i.e., indinavir (IC50 of 62 μM), nelfinavir (IC50 of 22 μM), ritonavir (IC50 of 5.2 μM), and saquinavir (IC50 of 8.3 μM) inhibited TEA uptake in HeLa cells expressing hOCT1. However, none of the HIV protease inhibitorstrans-stimulated [14C]TEA uptake, suggesting that they are poorly translocated by hOCT1. Nelfinavir, ritonavir, and saquinavir demonstrated an apparent “trans-inhibition” effect. No enhanced uptake of [14C]saquinavir was observed in hOCT1 DNA-transfected cells versus empty vector-transfected cells. These data suggest that HIV protease inhibitors are potent inhibitors, but poor substrates, of hOCT1. Some HIV protease inhibitors may potently inhibit the uptake and elimination of cationic drugs that are substrates for hOCT1, leading to potential drug-drug interactions. Other transporters, e.g., MDR1 and MRP1, in HIV-targeted cells may control the intracellular concentrations of HIV protease inhibitors.
Footnotes
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Send reprint requests to: Kathleen M. Giacomini, Ph.D., Department of Biopharmaceutical Sciences, University of California San Francisco, 513 Parnassus, S-926, San Francisco, CA 94143-0446. E-mail:kmg{at}itsa.ucsf.edu
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↵1 Present address: Metabolism and Pharmacokinetics, Bristol-Myers Squibb Company, Wallingford, Connecticut.
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↵2 Present address: Department of Drug Metabolism, Genentech, Inc., South San Francisco, California.
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This study was supported by National Institutes of Health Grants GM-57656 and GM-36780 (K.M.G.) and HL-53994 (D.L.K.). Lei Zhang was supported in part by the University of California San Francisco Chancellor's Graduate Research Fellowship.
- Abbreviations used are::
- TEA
- tetraethylammonium
- RT-PCR
- reverse transcriptase-polymerase chain reaction
- Cmax
- maximum plasma concentration
- CYP
- cytochrome P-450
- hOCT1
- human organic cation transporter 1
- P-gp
- P-glycoprotein
- Received May 7, 1999.
- Accepted November 15, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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