Apparent active transport of MDMA is not mediated by P-glycoprotein: a comparison with MDCK and Caco-2 monolayers.
Amphetamines and their methylenedioxy derivatives generically display similar behavioral, physiologic and toxic effects. Inconsistent pharmacokinetic and toxicity data for methylenedioxymethamphetamine (MDMA) may suggest that active drug transporters are interacting with these compounds, and thus altering drug absorption and tissue distribution. In vitro models of CNS accumulation and intestinal drug transport were used to assess efflux transport of MDMA. Madin-Darby kidney cell epithelial (MDCK) monolayers displayed a 4-fold increase in accumulation in the basolateral to apical orientation relative to the apical to basolateral orientation, although no differential accumulation was noted between MDCK-WT and MDCK-MDR1 monolayers. Caco-2 monolayers demonstrated an approximate 2-fold increase in accumulation of MDMA. Exposure of various inhibitors of active drug transporters demonstrated mixed results; ritonavir, progesterone and indomethacin produced an approximately 50% reduction of MDMA transport, while verapamil, MK-571 and probenecid had no effect. Based on these data, it is concluded that MDMA efflux is mediated via the activity of a transporter distinct from P-glycoprotein. The possible inhibitory effects of amphetamines on rhodamine-123 transport were also assessed. MDMA, methylenedioxyamphetamine, amphetamine and methamphetamine, at physiologically relevant concentrations, did not significantly alter the transport of rhodamine-123 in Caco-2 monolayers or the LS180 cell line, suggesting that these compounds do not alter the function of P-glycoprotein.
Bertelsen
Kirk M
KM
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USA.
Greenblatt
David J
DJ
von Moltke
Lisa L
LL
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D002460:Cell Line; D004285:Dogs; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000378:metabolism*; D011339:Probenecid / Q000494:pharmacology; D011374:Progesterone / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D020112:Rhodamine 123 / Q000378:metabolism; D019438:Ritonavir / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011422:Propionates; D011804:Quinolines; D020112:Rhodamine 123; D011374:Progesterone; C059141:verlukast; D014700:Verapamil; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D019438:Ritonavir; D011339:Probenecid; D007213:Indomethacin