![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 28, Issue 3, 329-334, March 2000
Department of Biopharmaceutical Sciences, University of California,
San Francisco, California (L.Z., W.G., D.L.K., K.M.G.); and Department
of Medicine, Division of Clinical Pharmacology, Stanford University
Medical Center, Stanford, California (C.B.W., T.F.B.)
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 inhibitors
trans-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.
This article has been cited by other articles:
|
|
 |
|
  G. Minuesa, C. Volk, M. Molina-Arcas, V. Gorboulev, I. Erkizia, P. Arndt, B. Clotet, M. Pastor-Anglada, H. Koepsell, and J. Martinez-Picado Transport of Lamivudine [(-)-{beta}-L-2',3'-Dideoxy-3'-thiacytidine] and High-Affinity Interaction of Nucleoside Reverse Transcriptase Inhibitors with Human Organic Cation Transporters 1, 2, and 3 J. Pharmacol. Exp. Ther., April 1, 2009; 329(1): 252 - 261. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Jung, C. Lehmann, A. Rubbert, M. Knispel, P. Hartmann, J. van Lunzen, H.-J. Stellbrink, G. Faetkenheuer, and D. Taubert Relevance of the Organic Cation Transporters 1 and 2 for Antiretroviral Drug Therapy in Human Immunodeficiency Virus Infection Drug Metab. Dispos., August 1, 2008; 36(8): 1616 - 1623. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Minuesa, S. Purcet, I. Erkizia, M. Molina-Arcas, M. Bofill, N. Izquierdo-Useros, F. J. Casado, B. Clotet, M. Pastor-Anglada, and J. Martinez-Picado Expression and Functionality of Anti-Human Immunodeficiency Virus and Anticancer Drug Uptake Transporters in Immune Cells J. Pharmacol. Exp. Ther., February 1, 2008; 324(2): 558 - 567. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Vidal, J. C. Domingo, J. Guallar, M. Saumoy, B. Cordobilla, R. Sanchez de la Rosa, M. Giralt, M. L. Alvarez, M. Lopez-Dupla, F. Torres, et al. In Vitro Cytotoxicity and Mitochondrial Toxicity of Tenofovir Alone and in Combination with Other Antiretrovirals in Human Renal Proximal Tubule Cells Antimicrob. Agents Chemother., November 1, 2006; 50(11): 3824 - 3832. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. C. Crossman, B. J. Druker, M. W. N. Deininger, M. Pirmohamed, L. Wang, and R. E. Clark hOCT 1 and resistance to imatinib Blood, August 1, 2005; 106(3): 1133 - 1134. [Full Text] [PDF]
|
|
|
|
 |
|
 J. Ford, S. H. Khoo, and D. J. Back The intracellular pharmacology of antiretroviral protease inhibitors J. Antimicrob. Chemother., December 1, 2004; 54(6): 982 - 990. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. H. Wright and W. H. Dantzler Molecular and Cellular Physiology of Renal Organic Cation and Anion Transport Physiol Rev, July 1, 2004; 84(3): 987 - 1049. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Gupta, Y. Zhang, J. D. Unadkat, and Q. Mao HIV Protease Inhibitors Are Inhibitors but Not Substrates of the Human Breast Cancer Resistance Protein (BCRP/ABCG2) J. Pharmacol. Exp. Ther., July 1, 2004; 310(1): 334 - 341. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Hasannejad, M. Takeda, K. Taki, H. J. Shin, E. Babu, P. Jutabha, S. Khamdang, M. Aleboyeh, M. L. Onozato, A. Tojo, et al. Interactions of Human Organic Anion Transporters with Diuretics J. Pharmacol. Exp. Ther., March 1, 2004; 308(3): 1021 - 1029. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Bednarczyk, S. Ekins, J. H. Wikel, and S. H. Wright Influence of Molecular Structure on Substrate Binding to the Human Organic Cation Transporter, hOCT1 Mol. Pharmacol., March 1, 2003; 63(3): 489 - 498. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. C. Williams, A. Liu, G. Knipp, and P. J. Sinko Direct Evidence that Saquinavir Is Transported by Multidrug Resistance-Associated Protein (MRP1) and Canalicular Multispecific Organic Anion Transporter (MRP2) Antimicrob. Agents Chemother., November 1, 2002; 46(11): 3456 - 3462. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Takeda, S. Khamdang, S. Narikawa, H. Kimura, M. Hosoyamada, S. H. Cha, T. Sekine, and H. Endou Characterization of Methotrexate Transport and Its Drug Interactions with Human Organic Anion Transporters J. Pharmacol. Exp. Ther., August 1, 2002; 302(2): 666 - 671. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Enomoto, M. Takeda, M. Shimoda, S. Narikawa, Y. Kobayashi, Y. Kobayashi, T. Yamamoto, T. Sekine, S. H. Cha, T. Niwa, et al. Interaction of Human Organic Anion Transporters 2 and 4 with Organic Anion Transport Inhibitors J. Pharmacol. Exp. Ther., June 1, 2002; 301(3): 797 - 802. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Takeda, S. Khamdang, S. Narikawa, H. Kimura, Y. Kobayashi, T. Yamamoto, S. H. Cha, T. Sekine, and H. Endou Human Organic Anion Transporters and Human Organic Cation Transporters Mediate Renal Antiviral Transport J. Pharmacol. Exp. Ther., March 1, 2002; 300(3): 918 - 924. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
