Department of Medicine, University of Western Ontario, London, ON, Canada.
Drug Metab Dispos. 2011 Mar;39(3):558-62. doi: 10.1124/dmd.110.036160. Epub 2010 Dec 8.
Tamoxifen is widely prescribed to patients with estrogen receptor-positive breast cancer, and it is a prodrug that requires bioactivation by cytochrome P450 enzymes CYP2D6 and 3A4 to generate the active metabolite, endoxifen. Large interpatient variability in endoxifen plasma levels has been reported, and polymorphisms in CYP2D6 have been implicated as a major determinant of such variability. However, little is known regarding the role of drug transporters such as P-glycoprotein [multidrug resistance 1 (MDR1), ATP-binding cassette B1 (ABCB1)] to endoxifen disposition and response. Therefore, we determined the ability of P-glycoprotein to transport endoxifen in vitro, using a polarized human P-glycoprotein-overexpressing cell line. Markedly higher transport of endoxifen was observed in the basal-to-apical direction, which was abrogated in the presence of the potent and specific P-glycoprotein inhibitor (2R)-anti-5-{3-[4-(10,11-difluoromethanodibenzo-suber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinoline trihydrochloride (LY335979). To validate the in vivo relevance of P-glycoprotein to endoxifen disposition, plasma and tissue concentrations were also determined in Mdr1a-deficient mice after oral administration of endoxifen. Plasma endoxifen levels did not significantly differ between wild-type and Mdr1a-deficient mice. However, brain concentrations of endoxifen were nearly 20-fold higher in Mdr1a-deficient mice compared to wild-type mice. Because P-glycoprotein is highly expressed at the blood-brain barrier and in some breast cancer tumors, variation in expression and function of this transporter may alter central nervous system entry and the attained intracellular concentration in such breast cancer cells and therefore may prove to be of relevance to therapeutic outcome.
他莫昔芬被广泛用于治疗雌激素受体阳性的乳腺癌患者，它是一种前药，需要细胞色素 P450 酶 CYP2D6 和 3A4 生物激活，生成活性代谢物，即依西美坦。据报道，依西美坦的血浆水平在患者间存在较大的变异性，CYP2D6 的多态性被认为是这种变异性的主要决定因素。然而，关于药物转运蛋白（如 P-糖蛋白[多药耐药 1（MDR1），ATP 结合盒 B1（ABCB1）]）对依西美坦处置和反应的作用知之甚少。因此，我们使用过表达人 P-糖蛋白的细胞系，在体外确定了 P-糖蛋白转运依西美坦的能力。依西美坦在基底-顶侧的转运明显较高，而在存在强效和特异性 P-糖蛋白抑制剂（2R）-反-5-[3-[4-（10,11-二氟甲氧基二苯并亚丁-5-基）哌嗪-1-基]-2-羟基丙氧基]喹啉三盐酸盐（LY335979）时则被阻断。为了验证 P-糖蛋白对依西美坦处置的体内相关性，还在口服依西美坦后测定了 Mdr1a 缺陷小鼠的血浆和组织浓度。野生型和 Mdr1a 缺陷型小鼠的血浆依西美坦水平无显著差异。然而，Mdr1a 缺陷型小鼠的脑组织中依西美坦浓度比野生型小鼠高近 20 倍。由于 P-糖蛋白在血脑屏障和一些乳腺癌肿瘤中高度表达，这种转运蛋白的表达和功能的变异可能会改变依西美坦进入中枢神经系统的途径以及此类乳腺癌细胞内的浓度，因此可能与治疗结果相关。
