The utility of endogenous glycochenodeoxycholate-3-sulfate and 4β-hydroxycholesterol to evaluate the hepatic disposition of atorvastatin in rats.
The utility of endogenous glycochenodeoxycholate-3-sulfate and 4β-hydroxycholesterol to evaluate the hepatic disposition of atorvastatin in rats.
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内源性甘鹅去氧胆酸-3-硫酸盐和4-β-羟基胆固醇评价阿托伐他汀在大鼠肝脏中的分布
DOI：
10.1016/j.ajps.2021.03.002
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发表时间：
2021-07
影响因子：
10.2
通讯作者：
Wu XA
中科院分区：
文献类型：
--
作者：
Ma Y;Xin M;Wen Y;Wang H;Zhang G;Dai J;Wu XA
肝脏是药物在体内分布的重要器官，如何准确评价肝脏清除率对合理给药至关重要。然而，基于肝功能和药物基因组学检测的药物剂量调整存在许多局限性。在这项研究中，我们评价了内源性甘氨鹅脱氧胆酸-3-硫酸盐（GCDCA-S）和4β-羟基胆固醇（4β-HC）血浆水平评估大鼠有机阴离子转运多肽（Oatps）介导的阿托伐他汀（ATV）肝脏摄取和Cyp 3a代谢的能力。单次注射Oatps抑制剂利福平（RIF）后，ATV及其代谢产物2-OH ATV和4-OH ATV的浓度显著增加。同时，血浆GCDCA-S水平也升高。单次注射Cyp 3a抑制剂酮康唑（KTZ）后，血浆ATV浓度显著升高，2-OH ATV浓度降低，与Cyp 3a对ATV的代谢一致。然而，尽管血浆4β-HC是胆固醇的Cyp 3a代谢产物，但其不受KTZ给药的影响。反复口服RIF后，ATV、2-OH ATV和4-OH ATV的血药浓度显著升高，ATV和GCDCA-S的肝摄取率降低。KTZ不影响ATV、2-OH ATV和4-OH ATV的血浆浓度，但显著降低总ATV和4-OH ATV的代谢率。而KTZ对4β-HC的血浆水平和肝脏代谢无明显影响。RIF对肝摄取GCDCA-S的抑制作用在7天洗脱后完全逆转。在ANIT诱导的肝损伤大鼠中，GCDCA-S的血浆浓度和肝摄取率分别与ATV的血浆水平和肝摄取率相关。这些结果表明，血浆GCDCA-S是评估Oatps介导的ATV肝摄取的敏感探针。然而，Cyp 3a介导的ATV代谢不能通过大鼠血浆4β-HC水平预测。
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 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 4β-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 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, Cyp3a-mediated metabolism of ATV was not predicted by plasma 4β-HC levels in rats.
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影响因子：
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