Abstract
Previous reports have indicated that in vitro biliary clearance (Clbiliary) determined in sandwich-cultured hepatocytes correlates well with in vivo Clbiliary for limited sets of compounds. This study was designed to estimate the in vitro Clbiliary in sandwich-cultured rat hepatocytes (SCRHs) of angiotensin II receptor blockers and HMG-CoA reductase inhibitors that undergo limited metabolism, to compare the estimated Clbiliary values with published in vivo Clbiliary data in rats, and to characterize the mechanism(s) of basolateral uptake and canalicular excretion of these drugs in rats. The average biliary excretion index (BEI) and in vitro Clbiliary values of olmesartan, valsartan, pravastatin, rosuvastatin, and pitavastatin were 15, 19, 43, 45, and 20%, respectively, and 1.7, 3.2, 4.4, 46.1, and 34.6 ml/min/kg, respectively. Clbiliary predicted from SCRHs, accounting for plasma unbound fraction, correlated with reported in vivo Clbiliary for these drugs. The rank order of Clbiliary values predicted from SCRHs was consistent with in vivo Clbiliary values. Bromosulfophthalein inhibited the uptake of all drugs. BEI and Clbiliary values of olmesartan, valsartan, pravastatin, and rosuvastatin, known multidrug resistance-associated protein (Mrp) 2 substrates, were reduced in SCRHs from Mrp2-deficient (TR-) compared with wild-type (WT) rats. Although Mrp2 plays a minor role in pitavastatin biliary excretion, pitavastatin BEI and Clbiliary were reduced in TR- compared with WT SCRHs; Bcrp expression in SCRHs from TR- rats was decreased. In conclusion, in vitro Clbiliary determined in SCRHs can be used to estimate and compare in vivo Clbiliary of compounds in rats and to characterize transport proteins responsible for their hepatic uptake and excretion.
Footnotes
-
This study was supported by the National Institutes of Health (Grant R01 GM41935). K.A. was supported by a scholarship from Daiichi-Sankyo.
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
doi:10.1124/jpet.108.138073.
-
ABBREVIATIONS: SCRH, sandwich-cultured rat hepatocyte; Clbiliary, biliary clearance; ARB, angiotensin II receptor blocker; Mrp, multidrug resistance-associated protein; EHBR, Eisai hyperbilirubinemic rat; BSP, bromosulfophthalein; E2-17βG, estradiol-17β-d-glucuronide; DMEM, Dulbecco's modified Eagle's medium; MEM, minimal essential medium; WT, wild type; TR-, Mrp2-deficient Wistar rat; HBSS, Hanks' balanced salt solution; BEI, biliary excretion index; fu,p, plasma unbound fraction; Bcrp, breast cancer resistance protein; Oatp, organic anion-transporting polypeptide.
- Received February 15, 2008.
- Accepted June 20, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|