P-Glycoprotein Mediates Efflux Transport of Darunavir in Human Intestinal Caco-2 and ABCB1 Gene-Transfected Renal LLC-PK1 Cell Lines

概要

Darunavir (DRV) is a nonpeptidic protease inhibitor (PI) approved for the treatment of human immunodeficiency virus (HIV) infection. DRV displays potent activity against HIV strains resistant to other available PIs. Coadministration with ritonavir (RTV) improves the oral bioavailability of DRV. Inhibition of cytochrome P450 by RTV has been proposed as a mechanism for enhanced DRV bioavailability. However, interaction of these drugs with intestinal transporters has not been elucidated. This study was performed to explore the involvement of P-glycoprotein in transcellular DRV transport in monolayers of human intestinal Caco-2 and in ABCB1 multidrug resistance 1, (MDR1) gene-transfected renal LLC-PK1 (L-MDR1) cell lines. Transepithelial transport of DRV in Caco-2 cell monolayers was 2-fold greater in the basal-to-apical direction compared to that in the opposite direction. RTV had a significant inhibitory effect on the efflux transport of DRV in Caco-2 cells. The apical-to-basal DRV transport was enhanced by P-glycoprotein inhibitors, cyclosporin A and verapamil, as well as multidrug resistance-related protein (MRP/ABCC) inhibitors, probenecid and MK571. Using the L-MDR1 cell line, basal-to-apical DRV transport was much greater than in the opposite direction. Furthermore, cyclosporin A markedly inhibited the basal-to-apical DRV transport. RTV significantly increased the apical-to-basal transport of DRV in L-MDR1 cells, but reduced transport in the opposite direction. DRV inhibited P-glycoprotein-mediated efflux of calcein-acetoxymethyl ester in L-MDR1 cells with the inhibitory potency of 121 μM. These findings suggest that DRV is a substrate of P-glycoprotein and MRP, most likely MRP2. RTV appeared to inhibit P-glycoprotein, thereby enhancing the absorptive transport of DRV.

著者

TANOUE Naomi Department of Specialized Dentistry, Nagasaki University Hospital of Medicine and Dentistry
FUJIMOTO Hiromi Department of Medicine, Cardiovascular Division, Osaka Ekisaikai Hospital
Fujimoto Hiromi Department Of Medicine Cardiovascular Division Osaka Ekisaikai Hospital
Watanabe Hiroshi Department of Cardiology, Niigata City General Hospital
Hamada Akinobu Department Of Pharmacy Kumamoto University Hospital
Mitsuya Hiroaki Department of Hematology and Infectious Diseases, Kumamoto University Hospital
Saito Hideyuki Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto
Higuchi Maiko Department of Pharmacy, Kumamoto University Hospital
Koh Yasuhiro Department of Hematology, Kumamoto University Graduate School of Medical and Pharmaceutical Sciences
Ghosh Arun Departments of Chemistry and Medicinal Chemistry, Purdue University
Higuchi Maiko Department Of Chemistry And Biotechnology Graduate School Of Engineering The University Of Tokyo
Mitsuya Hiroaki Department Of Hematology And Infectious Diseases Kumamoto University Graduate School Of Medical Scie
Watanabe Hiroshi Department Of Applied Chemistry And Bioengineering Graduate School Of Engineering Osaka City Univers
Watanabe Hiroshi Department Of Pharmacy Kumamoto University Hospital
Tanoue Naomi Department of Pharmacy, Kumamoto University Hospital
Koh Yasuhiro Department of Hematology, Kumamoto University Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University
Mitsuya Hiroaki Department of Hematology, Kumamoto University Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University
Fujimoto Hiromi Department of Pharmacy, Kumamoto University Hospital
Tanoue Naomi Department of Aesthetic Dentistry, Nagasaki University Hospital of Medicine and Dentistry
SAITO Hideyuki Department of Clinical Pharmaceutical Sciences, Faculty of Life Science, Kumamoto University

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