Ma Yanrong, Xin Mingyan, Wen Yuanjie, Wang Huan, Zhang Guoqiang, Dai Jianye, Wu Xin-An
School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
Department of Pharmacy, the First Hospital of Lanzhou University, Lanzhou 730000, China.
Asian J Pharm Sci. 2021 Jul;16(4):519-529. doi: 10.1016/j.ajps.2021.03.002. Epub 2021 Apr 6.
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.
肝脏是药物代谢的重要器官，因此如何准确评估肝脏清除率对于合理给药至关重要。然而，基于肝功能和药物基因组学检测进行药物剂量调整存在许多局限性。在本研究中，我们评估了内源性甘氨鹅去氧胆酸-3-硫酸盐（GCDCA-S）和4β-羟基胆固醇（4β-HC）血浆水平评估大鼠中有机阴离子转运多肽（Oatps）介导的阿托伐他汀（ATV）肝脏摄取以及Cyp3a介导的代谢的能力。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Cyp3a抑制剂酮康唑（KTZ）后，血浆ATV浓度显著增加，2-OH ATV浓度降低，这与Cyp3a对ATV的代谢一致。然而，尽管4β-HC是胆固醇的Cyp3a代谢产物，但血浆4β-HC不受KTZ治疗的影响。重复口服RIF后，ATV、2-OH ATV和4-OH ATV的血浆浓度显著增加，ATV和GCDCA-S的肝脏摄取率降低。KTZ不影响ATV、2-OH ATV和4-OH ATV的血浆浓度，但显著降低了总ATV和4-OH ATV的代谢率。然而KTZ并未改变4β-HC的血浆水平和肝脏代谢。RIF洗脱7天后，RIF对GCDCA-S肝脏摄取的抑制作用完全逆转。在ANIT诱导的肝损伤大鼠中，GCDCA-S的血浆浓度和肝脏摄取率分别与ATV的血浆水平和肝脏摄取相关。这些结果表明，血浆GCDCA-S是评估Oatps介导的ATV肝脏摄取的敏感探针。然而，大鼠血浆4β-HC水平无法预测Cyp3a介导的ATV代谢。
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