The influence of P-glycoprotein on morphine transport in Caco-2 cells. Comparison with paclitaxel

In vitro monolayer studies using Caco-2 cells were employed here to explore P-glycoprotein mediated transport of morphine. Bidirectional transport studies of 10-75 muM 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. (C) 2002 Elsevier Science B.V. All rights reserved.