How predictive are isolated perfused liver data of in vivo hepatic clearance? A meta-analysis of isolated perfused rat liver data.

IF 1.3 4区医学 Q4 PHARMACOLOGY & PHARMACY

Xenobiotica Pub Date : 2024-09-01 Epub Date: 2024-09-23 DOI:10.1080/00498254.2024.2404170

Julia A Schulz Pauly, J Cory Kalvass

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引用次数: 0

Abstract

Isolated perfused rat liver (IPRL) experiments have been used to answer clearance-related questions, including evaluating the impact of pathological and physiological processes on hepatic clearance (CL_H). However, to date, IPRL data has not been evaluated for in vivo CL_H prediction accuracy.In addition to a detailed overview of available IPRL literature, we present an in-depth analysis of the performance of IPRL in CL_H prediction.While the entire dataset poorly predicted CL_H (GAFE = 3.2; 64% within 3-fold), IPRL conducted under optimal experimental conditions, such as in the presence of plasma proteins and with a perfusion rate within 2-fold of physiological liver blood flow and corrected for unbound fraction in the presence of red blood cells, can accurately predict rat CL_H (GAFE = 2.0; 78% within 3-fold). Careful consideration of experimental conditions is needed to allow proper data analysis.Further, isolated perfused liver experiments in other species, including human livers, may allow us to address the current in vitro-in vivo disconnects of hepatic metabolic clearance and improve our methodology for CL_H predictions.

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离体灌注肝脏数据对体内肝清除率的预测性如何？离体灌注大鼠肝脏数据的荟萃分析。

离体灌注大鼠肝脏（IPRL）实验已被用于回答与清除率相关的问题，包括评估病理和生理过程对肝清除率（CLH）的影响。除了对现有 IPRL 文献进行详细概述外，我们还对 IPRL 在 CLH 预测中的表现进行了深入分析。2; 64% within 3-fold），但在最佳实验条件下进行的 IPRL（如在有血浆蛋白存在的情况下，灌注率为生理肝血流量的 2 倍以内，并在有红细胞存在的情况下对未结合部分进行校正）可以准确预测大鼠的 CLH（GAFE = 2.0; 78% within 3-fold）。此外，在其他物种（包括人类肝脏）中进行离体灌注肝脏实验可能会让我们解决目前肝脏代谢清除率体外-体内脱节的问题，并改进我们预测 CLH 的方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Xenobiotica 医学-毒理学

CiteScore

3.80

自引率

5.60%

发文量

审稿时长

2 months

期刊介绍： Xenobiotica covers seven main areas, including:General Xenobiochemistry, including in vitro studies concerned with the metabolism, disposition and excretion of drugs, and other xenobiotics, as well as the structure, function and regulation of associated enzymesClinical Pharmacokinetics and Metabolism, covering the pharmacokinetics and absorption, distribution, metabolism and excretion of drugs and other xenobiotics in manAnimal Pharmacokinetics and Metabolism, covering the pharmacokinetics, and absorption, distribution, metabolism and excretion of drugs and other xenobiotics in animalsPharmacogenetics, defined as the identification and functional characterisation of polymorphic genes that encode xenobiotic metabolising enzymes and transporters that may result in altered enzymatic, cellular and clinical responses to xenobioticsMolecular Toxicology, concerning the mechanisms of toxicity and the study of toxicology of xenobiotics at the molecular levelXenobiotic Transporters, concerned with all aspects of the carrier proteins involved in the movement of xenobiotics into and out of cells, and their impact on pharmacokinetic behaviour in animals and manTopics in Xenobiochemistry, in the form of reviews and commentaries are primarily intended to be a critical analysis of the issue, wherein the author offers opinions on the relevance of data or of a particular experimental approach or methodology