College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon, South Korea.
Fundam Clin Pharmacol. 2021 Dec;35(6):1100-1108. doi: 10.1111/fcp.12687. Epub 2021 May 21.
BACKGROUND & OBJECTIVES: Upregulation of hepatic P-glycoprotein (P-gp) expression has been reported in patients with non-alcoholic fatty liver disease (NAFLD) and rodent models thereof. Here, we explored the changes hepatic P-gp expression and activity in a NAFLD rat model and the effects thereof on the pharmacokinetics of digoxin (a probe substrate of P-gp).
Rats were fed a 1% (w/w) orotic acid-containing diet for 20 days to induce NAFLD; control rats received a normal diet. P-gp expression and biliary digoxin excretion were examined. The pharmacokinetics of digoxin were evaluated after it had been administered intravenously (10 μg·kg ) and orally (200 μg·kg ) to control and NAFLD rats.
The total areas under the plasma concentration-time curves (AUCs) of digoxin after intravenous and oral administration were significantly smaller (by 39.1% and 73.0%, respectively) in NAFLD rats because of faster biliary digoxin excretion, reflecting elevations of hepatic P-gp expression and activity. Notably, the steady-state volume of distribution rose by 98.2%, while extent of oral bioavailability fell by 55.5% in NAFLD rats.
This is the first study to report digoxin pharmacokinetic changes caused by hepatic P-gp upregulation in NAFLD. Further studies are needed to explore the clinical impact of enhanced P-gp-mediated biliary excretion on pharmacotherapies using P-gp substrates in patients with NAFLD.
已有研究报道，非酒精性脂肪性肝病（NAFLD）患者和相应的啮齿动物模型的肝 P 糖蛋白（P-gp）表达上调。本研究旨在探讨 NAFLD 大鼠模型中肝 P-gp 表达和活性的变化及其对地高辛（P-gp 的探针底物）药代动力学的影响。
采用 1%（w/w）乳清酸饲料喂养大鼠 20 天，诱导 NAFLD；对照组大鼠给予正常饮食。检测肝 P-gp 表达和胆汁中地高辛排泄。分别静脉（10μg·kg）和口服（200μg·kg）给予地高辛后，评价地高辛在对照组和 NAFLD 大鼠体内的药代动力学。
NAFLD 大鼠静脉和口服给予地高辛后的总血浆浓度-时间曲线下面积（AUCs）分别显著减小（分别减小 39.1%和 73.0%），这归因于胆汁中地高辛排泄增加，反映了肝 P-gp 表达和活性的上调。值得注意的是，NAFLD 大鼠的稳态分布容积增加了 98.2%，而口服生物利用度降低了 55.5%。
本研究首次报道了 NAFLD 中肝 P-gp 上调引起的地高辛药代动力学变化。需要进一步研究以探讨增强的 P-gp 介导的胆汁排泄对 NAFLD 患者使用 P-gp 底物的药物治疗的临床影响。
