Rodriguez Monica, Ortega Ignacio, Soengas Itziar, Suarez Elena, Lukas John C, Calvo Rosario
Department of Pharmacology, Faculty of Medicine, University of the Basque Country, Barrio Sarriena s/n 48940, Leioa, Vizcaya, Spain.
J Pharm Pharmacol. 2004 Mar;56(3):367-74. doi: 10.1211/0022357022782.
Methadone is an opiate drug that has been identified as an in-vitro substrate of the efflux pump P-glycoprotein (P-gp), active in the intestinal epithelium and in the blood-brain barrier (BBB), among other sites. The objective of this study was to test in vivo, in the rat model, the role of P-gp modulation on the analgesic effect and brain uptake of methadone, as well as identify the most relevant site via dual oral and intravenous (i.v.) experiments. The P-gp specific inhibitor (valspodar or PSC833) was preadministered (10 mg kg(-1) i.v.) to test groups. Analgesia was measured using the tailflick test. The ED50 for oral methadone (2, 3, 6 and 8 mg kg(-1)) decreased three-fold in valspodar groups compared with controls (2.23 +/- 0.002 mg kg(-1) and 6.07 +/- 0.07 mg kg(-1); P < 0.0001). The overall analgesic effect (% antinociception) was elevated 3.1 times in pretreated compared with control rats (90.65% +/- 0.22 vs 29.23% +/- 14.0; P < 0.01) after 6 mg kg(-1) oral methadone and 2.8 times after i.v. (0.35 mg kg(-1)) administration (91.75% +/- 4.27 vs 32.45% +/- 9.0; P < 0.01). The brain:plasma distribution ratio was higher in pretreated animals and AUCbrain (overall brain concentration) was 6 times higher after oral methadone and 4 times higher after i.v. compared with controls, disproportionally increased relative to plasma, implying an active process at the BBB. P-gp, and hence substrate comedication, plays a critical role in the evolution of the methadone analgesic effect and in its brain uptake, independent of the administration route.
美沙酮是一种阿片类药物，已被确定为外排泵P-糖蛋白（P-gp）的体外底物，P-糖蛋白在肠道上皮和血脑屏障（BBB）等部位发挥作用。本研究的目的是在大鼠模型中进行体内试验，测试P-糖蛋白调节对美沙酮镇痛效果和脑摄取的作用，并通过口服和静脉注射（i.v.）双重实验确定最相关的部位。向试验组预先给予P-糖蛋白特异性抑制剂（伐司朴达或PSC833，静脉注射10 mg kg⁻¹）。使用甩尾试验测量镇痛效果。与对照组相比，伐司朴达组口服美沙酮（2、3、6和8 mg kg⁻¹）的半数有效剂量（ED50）降低了三倍（分别为2.23±0.002 mg kg⁻¹和6.07±0.07 mg kg⁻¹；P<0.0001）。在给予6 mg kg⁻¹口服美沙酮后，预处理大鼠的总体镇痛效果（%抗伤害感受）比对照大鼠提高了3.1倍（90.65%±0.22对29.23%±14.0；P<0.01），静脉注射（0.35 mg kg⁻¹）后提高了2.8倍（91.75%±4.27对32.45%±9.0；P<0.01）。预处理动物的脑：血浆分布比率更高，口服美沙酮后全脑浓度（AUCbrain）比对照组高6倍，静脉注射后高4倍，相对于血浆不成比例地增加，这意味着血脑屏障存在主动转运过程。P-糖蛋白以及因此的底物合并用药，在美沙酮镇痛效果的演变及其脑摄取中起着关键作用，与给药途径无关。
