Abstract
Hepatic uptake and biliary excretion of olmesartan, a new angiotensin II blocker, were investigated in vitro using human hepatocytes, cells expressing uptake transporters and canalicular membrane vesicles, and in vivo using Eisai hyperbilirubinemic rats (EHBR), inherited multidrug resistance-associated protein (mrp2)-deficient rats. The uptake by human hepatocytes reached saturation with a Michaelis constant (Km) of 29.3 ± 9.9 μM. Both Na+-dependent and Na+-independent uptake of olmesartan by human hepatocytes were observed. The uptake by Na+-independent human liver-specific organic anion transporters OATP1B1 and OATP1B3 expressed in Xenopus laevis oocytes was also saturable, with Km values of 42.6 ± 28.6 and 71.8 ± 21.6 μM, respectively. The Na+-dependent taurocholate-cotransporting polypeptide expressed in HEK 293 cells did not transport olmesartan. The cumulative biliary excretion in EHBR was one-sixth compared with that in Sprague-Dawley rats. ATP-dependent uptake of olmesartan was observed in both human canalicular membrane vesicles (hCMVs) and MRP2-expressing vesicles. An MRP inhibitor, MK-571 ([[[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl][3-(dimethylamino)-3-oxopropyl]thio]methyl]thio]-propanoic acid) completely inhibited the uptake of olmesartan by hCMVs. In conclusion, the hepatic uptake and biliary excretion of olmesartan are mediated by transporters in humans. OATP1B1 and OATP1B3 are involved in hepatic uptake, at least in part, and MRP2 plays a dominant role in the biliary excretion.
Footnotes
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.105.008888.
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ABBREVIATIONS: AUC, area under the plasma concentration time curve; mrp/MRP, multidrug resistance-associated protein; EHBR, Eisai hyperbilirubinemic rat(s); OATP, organic anion-transporting polypeptide; NTCP, Na+-dependent taurocholate-cotransporting peptide; SNP, single nucleotide polymorphism; h, human; CMV, canalicular membrane vesicle; HEK, human embryonic kidney; DMEM, Dulbecco's modified Eagle's medium; E2-17G, estradiol-17β-d-glucuronide; MK-571, [[[3-[2-(7-chloro-quinolinyl)ethenyl]phenyl][3-(dimethylamino)-3-oxopropyl]thio]methyl]thio]-propanoic acid; CL, clearance; PS, permeability-surface area product; BQ-123, cyclo(d-Trp-d-Asp-l-Pro-d-Val)-l-Leu.
- Received December 12, 2005.
- Accepted February 17, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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