Therapeutics Research Centre, School of Pharmacy & Medical Sciences, Division of Health Sciences, University of South Australia Basil Hetzel Institute for Medical Research, Adelaide, SA, 5001, Australia.
Pharm Res. 2012 Jun;29(6):1658-69. doi: 10.1007/s11095-012-0690-z.
To explore how liver damage arising from cardio-hepatic syndromes in RHF affect the hepatic pharmacokinetics of basic drugs.
The hepatic pharmacokinetics of five selected basic drugs with different physicochemical properties were studied in IPRL from control rats and rats with RHF. Hepatic pharmacokinetic modelling was performed with a two-phase physiologically-based organ pharmacokinetic model with the vascular space and dispersion evaluated with the MID technique. The liver damage arising from RHF was assessed by changes in liver biochemistry and histopathology. The expression of various CYP isoforms was evaluated by real-time RT-PCR analysis.
Four of the five basic drugs had a significantly lower E in RHF rat livers compared to the control rat livers. Hepatic pharmacokinetic analysis showed that both the CL int and PS were significantly decreased in the RHF rat livers. Stepwise regression analysis showed that the alterations in the pharmacokinetic parameters (E, CL int and PS) can be correlated to the observed histopathological changes (NI, CYP concentration and FI) as well as to the lipophilicity of the basic drugs (logP app).
Serious hepatocellular necrosis and fibrosis induced by RHF affects both hepatic microsomal activity and hepatocyte wall permeability, leading to significant impairment in the hepatic pharmacokinetics of basic drugs.
探讨右心衰竭引起的心肝综合征导致的肝损伤如何影响基本药物的肝药代动力学。
本研究在 IPRL 中研究了具有不同物理化学性质的五种选定基本药物的肝药代动力学，分别在对照大鼠和 RHF 大鼠中进行。采用两阶段生理基于器官药代动力学模型进行肝药代动力学建模，用 MID 技术评估血管空间和弥散。通过肝功能和组织病理学变化来评估 RHF 引起的肝损伤。通过实时 RT-PCR 分析评估各种 CYP 同工酶的表达。
五种基本药物中有四种在 RHF 大鼠肝脏中的 E 值明显低于对照大鼠肝脏。肝药代动力学分析表明，RHF 大鼠肝脏中的 CL int 和 PS 均显著降低。逐步回归分析表明，药代动力学参数（E、CL int 和 PS）的变化可与观察到的组织病理学变化（NI、CYP 浓度和 FI）以及基本药物的亲脂性（logP app）相关。
RHF 引起的严重肝细胞坏死和纤维化既影响肝微粒体活性，又影响肝细胞壁通透性，导致基本药物肝药代动力学显著受损。
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