Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University, Japan.
J Pharm Pharmacol. 2012 Apr;64(4):496-504. doi: 10.1111/j.2042-7158.2011.01426.x. Epub 2011 Dec 29.
Opioids and anticancer compounds such as etoposide (ETP) are substrates of P-glycoprotein (P-gp), an ATP-dependent efflux pump. Chemotherapy compounds may impact on the analgesic effect of opioids such as morphine when the two drugs are co-administered. In this study, we used a mouse model to determine if there is a pharmacological interaction between ETP and morphine, focusing on the involvement of intestinal P-gp.
P-gp drug efflux activity was measured by an in-situ closed loop method with Rhodamine 123, a P-gp substrate. The analgesic effect of morphine was determined by the tail-flick test. Intestinal P-gp expression levels were determined by Western blot.
ETP and morphine significantly decreased the intestinal Rhodamine 123 efflux activity of P-gp. Oral morphine analgesia was significantly enhanced when co-administered with ETP. However, repeated pretreatment (7 days) with oral ETP significantly decreased the oral morphine-induced analgesia, in a cyclosporine A (a P-gp inhibitor) reversible manner. Furthermore, repeated ETP significantly up-regulated intestinal P-gp expression.
It may be important to consider aspects of therapeutic design such as the administration route or scheduling of drugs in patients receiving concurrent chemotherapy and opioid therapy to avoid pharmacokinetic interactions between the two agents.
阿片类药物和依托泊苷（ETP）等抗癌化合物是 P-糖蛋白（P-gp）的底物，P-gp 是一种依赖于 ATP 的外排泵。当两种药物同时给药时，化疗药物可能会影响阿片类药物如吗啡的镇痛效果。在本研究中，我们使用小鼠模型来确定 ETP 和吗啡之间是否存在药物相互作用，重点关注肠道 P-gp 的参与。
通过 Rhodamine 123 的原位闭环法测量 P-gp 药物外排活性，Rhodamine 123 是 P-gp 的底物。通过尾巴闪烁试验测定吗啡的镇痛作用。通过 Western blot 测定肠道 P-gp 表达水平。
ETP 和吗啡显着降低了 P-gp 的肠道 Rhodamine 123 外排活性。当与 ETP 同时给予时，口服吗啡的镇痛作用显着增强。然而，重复给予口服 ETP（7 天）预处理以环孢素 A（一种 P-gp 抑制剂）可逆转的方式显着降低了口服吗啡引起的镇痛作用。此外，重复给予 ETP 显着上调了肠道 P-gp 的表达。
在接受同时进行化疗和阿片类药物治疗的患者中，考虑治疗设计的方面（如给药途径或药物安排）可能很重要，以避免两种药物之间的药代动力学相互作用。
