The utility of endogenous glycochenodeoxycholate-3-sulfate and 4β-hydroxycholesterol to evaluate the hepatic disposition of atorvastatin in rats

The liver is an important organ for drugs disposition,and thus how to accurately evaluate hepatic clearance is essential for proper drug dosing.However,there are many limitations in drug dosage adjustment based on liver function and pharmacogenomic testing.In this study,we evaluated the ability of endogenous glycochenodeoxycholate-3-sulfate(GCDCA-S)and 4β-hydroxycholesterol(4β-HC)plasma levels to evaluate organic anion-transporting polypeptide(Oatps)-mediated hepatic uptake and Cyp3 a-meidated metabolism of atorvastatin(ATV)in rats.The concentration of ATV and its metabolites,2-OH ATV and 4-OH ATV,was markedly increased after a single injection of rifampicin(RIF),an inhibitor of Oatps.Concurrently,plasma GCDCA-S levels were also elevated.After a single injection of the Cyp3 a inhibitor ketoconazole(KTZ),plasma ATV concentrations were significantly increased and 2-OH ATV concentrations were decreased,consistent with the metabolism of ATV by Cyp3 a.However,plasma 4β-HC was not affected by KTZ treatment despite it being a Cyp3 a metabolite of cholesterol.After repeated oral administration of RIF,plasma concentrations of ATV,2-OH ATV and 4-OH ATV were markedly increased and the hepatic uptake ratio of ATV and GCDCA-S was decreased.KTZ did not affect plasma concentrations of ATV,2-OH ATV and 4-OH ATV,but significantly decreased the metabolic ratio of total and 4-OH ATV.However,the plasma level and hepatic metabolism of 4β-HC were not changed by KTZ.The inhibition of hepatic uptake of GCDCA-S by RIF was fully reversed after a 7-d washout of RIF.Plasma concentration and hepatic uptake ratio of GCDCA-S were correlated with the plasma level and hepatic uptake of ATV in rats with ANIT-induced liver injury,respectively.These results demonstrate that plasma GCDCA-S is a sensitive probe for the assessment of Oatps-mediated hepatic uptake of ATV.However,Cyp3 a-mediated metabolism of ATV was not predicted by plasma 4β-HC levels in rats.

Potential mechanism of cholagogic effect about Gardenia Jasminoides Ellis(Zhizi)-mediated increase of bile acids urinary excretion in normal rats

Objectives： Gardenia Jasminoides Ellis（Zhizi）, belonging to Rubiaceae family, has been traditionally used for treatment cholestasis and jaundice for centuries in Asian countries. In the theory of Traditional Chinese Medicines, Zhizi could dispel dampness and heat via the urine to execute its choleretic effects. However, the potential molecular mechanism has been still poorly clarified. Here, we investigated the effect of different dose of Zhizi aqueous extract powder（0.3 g/kg/d and 0.9 g/kg/d） on urinary excretion of bile acids（BAs）, and defined the potential mechanism via renal BAs efflux transporters Mrp2 and Mrp4 in normal rats.Methods： Male Wistar rats were orally administrated with 0.3 or 0.9 g/kg/d dose of Zhizi aqueous extract powder for 2 weeks, then body weight, serum aminotransferase, total BAs concentrations in liver, bile,serum, kidney and urine, 1 h bile flow, 12-h urinary volume, biliary and urinary excretion amount of total BAs as well as protein expression of major renal BAs efflux transporter Mrp2 and Mrp4, were all evaluated.Results： Zhizi especially the high dose of Zhizi aqueous extract powder could reduce hepatic total BAs concentration. Additionally, bile flow and biliary excretion had no significant difference, but the remarkable increasing urinary excretion of BAs and 2 to 3 folds up-regulated renal Mrp2 expression were observed after administrated with Zhizi as compared with the control group.Conclusion： The findings indicate that Zhizi reduces hepatic total BAs level by increasing urinary excretion rather than the biliary excretion of BAs, which, in turn ascribed to elevated protein expression of Mrp2 at apical membrane of renal tubular epithelial cells.