title: Active transport of the angiotensin-II antagonist losartan and its main metabolite EXP 3174 across MDCK-MDR1 and caco-2 cell monolayers.
abstract: 1. We studied the functional interaction between transport and metabolism by comparing the transport of losartan and its active metabolite EXP 3174 (EXP) across cell monolayers. 2. Epithelial layers of Caco-2 cells as well as MDR1, MRP-1 and MRP-2 overexpressing cells, in comparison to the respective wildtypes, were used to characterize the transcellular transport of losartan and EXP. 3. Losartan transport in MDCK-MDR1 and Caco-2 cells was saturable and energy-dependent with a significantly greater basolateral-to-apical (B/A) than apical-to-basolateral (A/B) flux (ratio=31+/-1 in MDCK-MDR1 and ratio 4+/-1 in Caco-2 cells). The B/A flux of losartan was inhibited by cyclosporine and vinblastine, inhibitors of P-glycoprotein and MRP. In contrast, no active losartan transport was observed in MRP-1 or MRP-2 overexpressing cells. 4. The metabolite was only transported in Caco-2 cells with a B/A-to-A/B ratio of 5+/-1, while lacking active transport in the MDR1, MRP-1 or MRP-2 overexpressing cells. The B/A flux of EXP was significantly inhibited by cyclosporine and vinblastine. 5. In conclusion, losartan is transported by P-glycoprotein and other intestinal transporters, that do not include MRP-1 and MRP-2. In contrast, the carboxylic acid metabolite is not a P-glycoprotein substrate, but displays considerably higher affinity for other transporters than losartan, that again most probably do not include MRP-1 and MRP-2.
authors.affiliation: Department of Biopharmaceutical Sciences, School of Pharmacy, University of California, San Francisco, CA 94143-0446, USA.
authors.forename: A
authors.initials: A
authors.lastname: Soldner
authors.forename: L Z
authors.initials: LZ
authors.lastname: Benet
authors.forename: E
authors.initials: E
authors.lastname: Mutschler
authors.forename: U
authors.initials: U
authors.lastname: Christians
mesh_terms: D019297:2,4-Dinitrophenol / Q000494:pharmacology; D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000378:metabolism*; D000963:Antimetabolites / Q000494:pharmacology; D001693:Biological Transport, Active / Q000187:drug effects; D018938:Caco-2 Cells; D002460:Cell Line; D002853:Chromatography, Liquid; D004285:Dogs; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D018374:LLC-PK1 Cells; D019808:Losartan / Q000378:metabolism*; D013058:Mass Spectrometry; D000089762:Multidrug Resistance-Associated Protein 2; D013552:Swine; D013696:Temperature; D013777:Tetrazoles / Q000378:metabolism*
chemical_list: C000715087:ABCC2 protein, human; D000889:Anti-Arrhythmia Agents; D000963:Antimetabolites; D007093:Imidazoles; D000089762:Multidrug Resistance-Associated Protein 2; D013777:Tetrazoles; D000804:Angiotensin II; C066026:losartan carboxylic acid; D019808:Losartan; D019297:2,4-Dinitrophenol