Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University, Minatojima, Chuo-ku, Japan.
Eur J Pharm Sci. 2012 Dec 18;47(5):934-40. doi: 10.1016/j.ejps.2012.08.019. Epub 2012 Sep 13.
In early palliative care, drug-drug interactions between opioids and anticancer agents may be caused by combined treatment with these drugs. We previously reported that repeated administration of oral etoposide (ETP), an anticancer drug that is a substrate of P-glycoprotein (P-gp), caused attenuation of the analgesic effect of oral morphine through up-regulation of intestinal P-gp. Recent studies have revealed that RhoA, a small G-protein, is involved in the regulation of P-gp expression and activity. Moreover, RhoA is known to be involved in various signaling pathways in response to anticancer drugs. Here, we examined the involvement of RhoA in the changes in ileal P-gp protein expression and activity induced by repeated orally administered ETP. Ileal P-gp and RhoA protein expression levels were analyzed using western blot analysis. The efflux activity of ileal P-gp was measured using the in situ closed loop method. The analgesic effect of oral morphine was determined with a tail-flick test. Repeated oral ETP significantly increased the activity of RhoA in association with up-regulation of P-gp protein expression and activity in the ileum. Interestingly, inhibition of RhoA activation by rosuvastatin prevented these effects. Furthermore, ETP-induced attenuation of the analgesic effect of oral morphine was also suppressed by rosuvastatin. RhoA activation induced by repeated oral ETP administration may be involved in the up-regulation of ileal P-gp protein expression and activity, leading to a decrease in the analgesic effect of oral morphine.
在姑息治疗早期，阿片类药物和抗癌药物之间的药物-药物相互作用可能是由于这些药物的联合治疗引起的。我们之前报道过，重复给予口服依托泊苷（ETP），一种细胞毒药物，是 P 糖蛋白（P-gp）的底物，通过上调肠道 P-gp 导致口服吗啡的镇痛作用减弱。最近的研究表明，RhoA，一种小 G 蛋白，参与 P-gp 表达和活性的调节。此外，RhoA 已知参与对抗癌药物的各种信号转导途径。在这里，我们研究了 RhoA 是否参与了重复口服给予 ETP 诱导的回肠 P-gp 蛋白表达和活性的变化。使用 Western blot 分析分析回肠 P-gp 和 RhoA 蛋白表达水平。使用原位闭环法测量回肠 P-gp 的外排活性。使用尾巴闪烁试验测定口服吗啡的镇痛作用。重复口服 ETP 显著增加了 RhoA 的活性，同时上调了回肠 P-gp 蛋白的表达和活性。有趣的是，罗苏伐他汀抑制 RhoA 激活可防止这些作用。此外，罗苏伐他汀还抑制了 ETP 诱导的口服吗啡镇痛作用的减弱。重复口服 ETP 给药诱导的 RhoA 激活可能参与了回肠 P-gp 蛋白表达和活性的上调，导致口服吗啡的镇痛作用减弱。
