دورية أكاديمية
The utility of endogenous glycochenodeoxycholate-3-sulfate and 4 β-hydroxycholesterol to evaluate the hepatic disposition of atorvastatin in rats.
| العنوان: | The utility of endogenous glycochenodeoxycholate-3-sulfate and 4 β-hydroxycholesterol to evaluate the hepatic disposition of atorvastatin in rats. |
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| المؤلفون: | Yanrong Ma, Mingyan Xin, Yuanjie Wen, Huan Wang, Guoqiang Zhang, Jianye Dai, Xin-An Wu |
| المصدر: | Asian Journal of Pharmaceutical Sciences; Jul2021, Vol. 16 Issue 4, p519-529, 11p |
| مصطلحات موضوعية: | HYDROXYCHOLESTEROLS, RATS, ATORVASTATIN, CYTOCHROME P-450 CYP3A, DRUG dosage, ESSENTIAL drugs |
| مستخلص: | 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 4 β-hydroxycholesterol (4 β-HC) plasma levels to evaluate organic anion-transporting polypeptide (Oatps)-mediated hepatic uptake and Cyp3a-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 Cyp3a inhibitor ketoconazole (KTZ), plasma ATV concentrations were significantly increased and 2-OH ATV concentrations were decreased, consistent with the metabolism of ATV by Cyp3a. However, plasma 4 β-HC was not affected by KTZ treatment despite it being a Cyp3a 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 4 β-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, Cyp3a-mediated metabolism of ATV was not predicted by plasma 4 β-HC levels in rats. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: | Complementary Index |
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