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. 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.
Crowe
Andrew
A
School of Pharmacy, Curtin University of Technology, GPO Box U1987, 6845, Perth, Australia. A.P.Crowe@curtin.edu.au
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000502:physiology*; D000701:Analgesics, Opioid / Q000378:metabolism / Q000493:pharmacokinetics*; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000493:pharmacokinetics*; D001692:Biological Transport / Q000187:drug effects; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D018938:Caco-2 Cells / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D003524:Cyclosporins / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019833:Genistein / Q000494:pharmacology; D005978:Glutathione / Q000494:pharmacology; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D009020:Morphine / Q000378:metabolism / Q000493:pharmacokinetics*; D017239:Paclitaxel / Q000378:metabolism / Q000493:pharmacokinetics*; D011339:Probenecid / Q000494:pharmacology; D011374:Progesterone / Q000494:pharmacology; D013997:Time Factors; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000701:Analgesics, Opioid; D000972:Antineoplastic Agents, Phytogenic; D003524:Cyclosporins; D011374:Progesterone; D019328:Buthionine Sulfoximine; D009020:Morphine; D016572:Cyclosporine; D014700:Verapamil; D019833:Genistein; D005978:Glutathione; D017239:Paclitaxel; D011339:Probenecid; C070272:valspodar; D007213:Indomethacin