Crowe Andrew
School of Pharmacy, Curtin University of Technology, GPO Box U1987, 6845, Perth, Australia.
Eur J Pharmacol. 2002 Apr 5;440(1):7-16. doi: 10.1016/s0014-2999(02)01366-3.
In vitro monolayer studies using Caco-2 cells were employed here to explore P-glycoprotein mediated transport of morphine. Bi-directional transport studies of 10-75 microM morphine showed efflux to be twofold higher than influx (4 x 10(-6) compared to 2 x 10(-6) cm/s) and cellular accumulation in the efflux direction was eightfold higher. The cyclosporin analogue (PSC-833) equilibrated morphine transport in both directions. Depletion of intracellular glutathione had a greater effect on increasing cellular morphine accumulation than P-glycoprotein inhibitors, suggesting a role for glutathione in morphine transport. P-glycoprotein had a substantially greater effect on paclitaxel accumulation, efflux and bi-directional transport than for morphine. Paclitaxel transport was below detection (<0.1 x 10(-6) cm/s) in the influx direction, yet efflux was very high (18.4 x 10(-6) cm/s) and P-glycoprotein inhibition increased accumulation >100-fold. These results reinforce the substantial role P-glycoprotein has in paclitaxel transport. Conversely, P-glycoprotein regulated morphine transport is weak. Nevertheless, morphine transport rates could be doubled when administered with P-glycoprotein substrates. Therefore, increased analgesia through P-glycoprotein inhibition should be possible.
本研究采用Caco - 2细胞进行体外单层研究，以探讨P - 糖蛋白介导的吗啡转运。对10 - 75 μM吗啡的双向转运研究表明，外流转运比内流转运高两倍（外流转运速率为4×10⁻⁶ cm/s，内流转运速率为2×10⁻⁶ cm/s），且外流转运方向的细胞蓄积高八倍。环孢素类似物（PSC - 833）使吗啡在两个方向上的转运达到平衡。细胞内谷胱甘肽的耗竭对增加细胞吗啡蓄积的影响比P - 糖蛋白抑制剂更大，表明谷胱甘肽在吗啡转运中发挥作用。P - 糖蛋白对紫杉醇蓄积、外流转运和双向转运的影响比对吗啡的影响大得多。紫杉醇的内流转运低于检测限（<0.1×10⁻⁶ cm/s），但其外流转运非常高（18.4×10⁻⁶ cm/s），P - 糖蛋白抑制使紫杉醇蓄积增加>100倍。这些结果强化了P - 糖蛋白在紫杉醇转运中的重要作用。相反，P - 糖蛋白对吗啡转运的调节作用较弱。然而，与P - 糖蛋白底物一起给药时，吗啡转运速率可提高一倍。因此，通过抑制P - 糖蛋白来增强镇痛效果应该是可行的。
