School of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan 406040, ROC.
Department of Pharmacy, China Medical University Hospital, Taichung, Taiwan 404327, ROC.
J Food Drug Anal. 2024 Mar 15;32(1):103-111. doi: 10.38212/2224-6614.3495.
Magnoliae Officinalis Cortex (MOC), an herbal drug, contains polyphenolic lignans mainly magnolol (MN) and honokiol (HK). Methotrexate (MTX), a critical drug for cancers and autoimmune deseases, is a substrate of multidrug resistance-associated protein 2 (MRP2) and breast cancer resistance protein (BCRP). This study investigated the effect of coadministration of MOC on the pharmacokinetics of MTX and relevant mechanisms. Sprague-Dawley rats were orally administered MTX alone and with single dose (2.0 and 4.0 g/kg) and repeated seven doses of MOC (2.0 g/kg thrice daily for 2 days, the 7th dose given at 0.5 h before MTX). The serum concentrations of MTX were determined by a fluorescence polarization immunoassay. The results showed that a single dose of MOC at 2.0 g/kg significantly increased the AUC and MRT of MTX by 352% and 308%, and a single dose at 4.0 g/kg significantly enhanced the AUC and MRT by 362% and 291%, respectively. Likewise, repeated seven doses of MOC at 2.0 g/kg significantly increased the AUC and MRT of MTX by 461% and 334%, respectively. Mechanism studies indicated that the function of MRP2 was significantly inhibited by MN, HK and the serum metabolites of MOC (MOCM), whereas BCRP was not inhibited by MOCM. In conclusion, coadministration of MOC markedly enhanced the systemic exposure and mean residence time of MTX through inhibiting the MRP2-mediated excretion of MTX.
厚朴（Magnoliae Officinalis Cortex，MOC）为一种草药，主要含有多酚类木脂素，包括厚朴酚（MN）和和厚朴酚（HK）。甲氨蝶呤（Methotrexate，MTX）是一种治疗癌症和自身免疫性疾病的关键药物，它是多药耐药相关蛋白 2（MRP2）和乳腺癌耐药蛋白（BCRP）的底物。本研究考察了厚朴同时给药对 MTX 药代动力学的影响及其相关机制。SD 大鼠分别给予 MTX 单药和厚朴（2.0 和 4.0 g/kg）单次及重复 7 次给药（每天 3 次，每次 2.0 g/kg，连续 2 天，第 7 次给药在 MTX 前 0.5 h 给予）。采用荧光偏振免疫分析法测定 MTX 血清浓度。结果表明，厚朴 2.0 g/kg 单次给药使 MTX 的 AUC 和 MRT 分别显著增加 352%和 308%，4.0 g/kg 单次给药使 AUC 和 MRT 分别显著增加 362%和 291%。同样，厚朴 2.0 g/kg 重复 7 次给药使 MTX 的 AUC 和 MRT 分别显著增加 461%和 334%。机制研究表明，MN、HK 和厚朴的血清代谢产物（MOCM）显著抑制了 MRP2 介导的 MTX 排泄，而 BCRP 未被 MOCM 抑制。总之，厚朴共给药通过抑制 MRP2 介导的 MTX 排泄，显著增强了 MTX 的全身暴露和平均停留时间。
