School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR.
State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
Pharm Res. 2023 Nov;40(11):2627-2638. doi: 10.1007/s11095-023-03590-1. Epub 2023 Sep 5.
Our previous screening studies identified Oroxylin A (OXA) as a strong inhibitor on the carboxyolesterase mediated hydrolysis of irinotecan to SN-38. The current study employed a whole-body physiologically based pharmacokinetic (PBPK) modeling approach to investigate the underlying mechanisms of the carboxylesterase-mediated pharmacokinetics interactions between irinotecan and OXA in rats.
Firstly, rats received irinotecan intravenous treatment at 35 μmol/kg without or with oral OXA pretreatment (2800 μmol/kg) daily for 5 days. On day 5, blood and tissues were collected for analyses of irinotecan/SN-38 concentrations and carboxylesterase expression. In addition, effects of OXA on the enzyme kinetics of irinotecan hydrolysis and unbound fractions of irinotecan and SN-38 in rat plasma, liver and intestine were also determined. Finally, a PBPK model that integrated the physiological parameters, enzyme kinetics, and physicochemical properties of irinotecan and OXA was developed.
Our PBPK model could accurately predict the pharmacokinetic profiles of irinotecan/SN-38, with AUC and C values within ±27% of observed values. When OXA was included as a carboxylesterase inhibitor, the model could also predict the irinotecan/SN-38 plasma concentrations within twofold of those observed. In addition, the PBPK model indicated inhibition of carboxylesterase-mediated hydrolysis of irinotecan in the intestinal mucosa as the major underlying mechanism for the pharmacokinetics interactions between irinotecan and OXA.
A whole-body PBPK model was successfully developed to not only predict the impact of oral OXA pretreatment on the pharmacokinetics profiles of irinotecan but also reveal its inhibition on the intestinal carboxylesterase as the major underlying mechanism.
我们之前的筛选研究表明，白杨素（OXA）是强烈抑制羧酸酯酶介导伊立替康水解为 SN-38 的抑制剂。本研究采用全身体生理基于药代动力学（PBPK）建模方法，研究羧酸酯酶介导的伊立替康与 OXA 在大鼠体内药代动力学相互作用的潜在机制。
首先，大鼠静脉注射伊立替康 35μmol/kg，连续 5 天每天给予或不给予口服 OXA 预处理（2800μmol/kg）。第 5 天，采集血液和组织，分析伊立替康/SN-38 浓度和羧酸酯酶表达。此外，还测定了 OXA 对伊立替康水解的酶动力学和伊立替康及 SN-38 在大鼠血浆、肝脏和肠道中的未结合分数的影响。最后，建立了一个整合了伊立替康和 OXA 的生理参数、酶动力学和物理化学特性的 PBPK 模型。
我们的 PBPK 模型可以准确预测伊立替康/SN-38 的药代动力学特征，AUC 和 C 值与观察值的偏差在 ±27%以内。当将 OXA 作为羧酸酯酶抑制剂包含在内时，模型也可以预测伊立替康/SN-38 的血浆浓度在观察值的两倍以内。此外，PBPK 模型表明，OXA 作为羧酸酯酶抑制剂，抑制了肠道黏膜中伊立替康的水解，这是伊立替康与 OXA 之间药代动力学相互作用的主要潜在机制。
成功建立了一个全身体 PBPK 模型，不仅可以预测口服 OXA 预处理对伊立替康药代动力学特征的影响，还揭示了其对肠道羧酸酯酶的抑制作用是主要的潜在机制。
