Numerous studies have previously been conducted with the impulse-response isolated perfused rat liver (IR-IPRL) to establish the role of both physiological and physicochemical factors in determining solutes' pattern of hepatic disposition, however the impact of optical isomerism on hepatic disposition has hardly been studied using this methodology. In this study, the IR-IPRL was used to assess the extent of stereoselectivity exhibited by the kinetic processes involved in the hepatic disposition of the diastereomeric acyl glucuronides of (R)- and (S)-2-phenylpropionic acid (i.e. (R)- and (S)-PPAG). Moment and model-dependent (distributed model and axial dispersion model) analyses were conducted of the hepatic outflow profiles generated upon bolus administration of (R)-(14)C-PPAG or (S)-(14)C-PPAG and 3H-Sucrose (used as a marker of the hepatic vascular space) into the portal inflow of isolated perfused livers of male Sprague-Dawley rats (n = 4). Significant differences between (R)- and (S)-PPAG were apparent in the pharmacokinetic parameters defining the total hepatic disposition of the two diastereomers, the most marked being the hepatic availabilities, where the value for (S)-PPAG (0.721 +/- 0.059) was significantly lower than that of (R)-PPAG (0.909 +/- 0.042). The distributed and axial dispersion model analyses suggested that the more extensive hepatic extraction of (S)-PPAG was (at least in part) due to the higher sinusoidal membrane permeability-surface area product (PS UPT) of the diastereomer, and this has been considered in light of the emerging evidence regarding the role of hepatocellular membrane transport mechanisms. Furthermore, given the potential immunogenicity of acyl glucuronides (through covalent binding to plasma and intracellular proteins), the results of this study suggest that diastereomeric glucuronides may exhibit differing toxicity due to differences in their access to intracellular proteins.

中文翻译：

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模型非对映体酰基葡萄糖醛酸苷的立体选择性肝处置。

以前已经对冲激响应的离体灌流大鼠肝脏（IR-IPRL）进行了大量研究，以确定生理和理化因素在确定溶质的肝处置模式中的作用，但是光学异构对肝处置的影响几乎没有使用这种方法进行了研究。在这项研究中，IR-IPRL用于评估由（R）-和（S）-2-苯基丙酸（即（R））的非对映体酰基葡萄糖醛酸苷的肝脏处置所涉及的动力学过程所显示的立体选择性程度-和（S）-PPAG）。对（R）-（14）C-PPAG或（S）-（14）C-PPAG和3H-进行大剂量给药时产生的肝流出曲线进行了矩和模型相关的分析（分布模型和轴向弥散模型）蔗糖（用作肝血管空间的标记）进入雄性Sprague-Dawley大鼠（n = 4）的离体灌注肝脏的门静脉流入。（R）-和（S）-PPAG之间的显着差异在定义这两种非对映异构体的总肝脏分布的药代动力学参数中很明显，其中最明显的是肝利用度，其中（S）-PPAG的值（0.721 + / -0.059）显着低于（R）-PPAG（0.909 +/- 0.042）。分布和轴向弥散模型分析表明，（S）-PPAG的肝提取范围更大（至少部分是由于非对映异构体的正弦膜通透性表面积乘积（PS UPT）更高，考虑到有关肝细胞膜转运机制的作用的新证据考虑。此外，鉴于酰基葡糖醛酸苷具有潜在的免疫原性（通过共价结合至血浆和细胞内蛋白），该研究结果表明，由于其进入胞内蛋白的途径不同，非对映体葡糖醛酸苷可能表现出不同的毒性。