Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Amherst, 14260, USA.
Biopharm Drug Dispos. 2010 Jul;31(5-6):340-50. doi: 10.1002/bdd.717.
The aim of our study was to investigate the effect of biochanin A on the accumulation and transport of mitoxantrone in breast cancer resistance protein (BCRP)-expressing normal cells and its impact on the pharmacokinetics (PK) and tissue distribution of mitoxantrone. In accumulation studies, the intracellular level of mitoxantrone was significantly increased in the presence of 2.5 or 25 microM of biochanin A in both murine and human BCRP-expressing Madin-Darby canine kidney (MDCK) cells, with no effect in corresponding MDCK/Mock cells. In bi-directional transport studies, the P(app,B-A) value of mitoxantrone with biochanin A co-treatment was much lower (6.66+/-0.84x10(-7) cm/s) than that in the absence of biochanin A (21.4+/-4.14x10(-7) cm/s), indicating inhibition of Bcrp1-mediated efflux. To evaluate whether our in vitro results might translate into an in vivo interaction, mitoxantrone PK and tissue distribution, with and without co-administration of biochanin A, was investigated. In contrast to our in vitro results, biochanin A (10 mg/kg, i.v.) had no impact on the concentration of mitoxantrone in plasma and most tissues collected (brain, heart, liver and lung). Surprisingly, the concentrations of mitoxantrone in spleen and kidney were even decreased when biochanin A was co-administered. Interestingly, it was found that the intracellular fluorescence of mitoxantrone was decreased 31.9% when co-incubated with 10 microM biochanin A in P-glycoprotein (P-gp) expressing MCF-7/ADR cells, indicating potential P-gp stimulation. The species difference of the inhibitory effect of biochanin A on BCRP, the extensive metabolism of biochanin A, as well as the stimulation effect of biochanin A on P-gp, may contribute to this in vitro-in vivo disconnect.
我们研究的目的是研究大豆苷元 A 对乳腺癌耐药蛋白（BCRP）表达正常细胞中米托蒽醌积累和转运的影响及其对米托蒽醌药代动力学（PK）和组织分布的影响。在积累研究中，在存在 2.5 或 25μM 大豆苷元 A 的情况下，米托蒽醌在两种鼠和人 BCRP 表达的 Madin-Darby 犬肾（MDCK）细胞中的细胞内水平均显著增加，而在相应的 MDCK/Mock 细胞中则没有影响。在双向转运研究中，与无大豆苷元 A 共处理时相比，米托蒽醌与大豆苷元 A 共处理时的 P(app,B-A) 值（6.66+/-0.84x10(-7)cm/s）要低得多（21.4+/-4.14x10(-7)cm/s），表明抑制了 Bcrp1 介导的外排。为了评估我们的体外结果是否可能转化为体内相互作用，研究了米托蒽醌 PK 和组织分布，以及有无大豆苷元 A 的共给药。与我们的体外结果相反，大豆苷元 A（10mg/kg，iv）对血浆中和大多数收集的组织（脑、心、肝和肺）中米托蒽醌的浓度没有影响。令人惊讶的是，当共给予大豆苷元 A 时，脾脏和肾脏中米托蒽醌的浓度甚至降低。有趣的是，当与 10μM 大豆苷元 A 共孵育时，在表达 P-糖蛋白（P-gp）的 MCF-7/ADR 细胞中发现米托蒽醌的细胞内荧光降低了 31.9%，表明存在潜在的 P-gp 刺激作用。大豆苷元 A 对 BCRP 的抑制作用的种属差异、大豆苷元 A 的广泛代谢以及大豆苷元 A 对 P-gp 的刺激作用可能导致了这种体外-体内不连接。
