Differential involvement of P-glycoprotein (ABCB1) in permeability, tissue distribution, and antinociceptive activity of methadone, buprenorphine, and diprenorphine: in vitro and in vivo evaluation.
Conclusions based on either in vitro or in vivo approach to evaluate the P-gp affinity status of opioids may be misleading. For example, in vitro studies indicated that fentanyl is a P-gp inhibitor while in vivo studies indicated that it is a P-gp substrate. Quite the opposite was evident for meperidine. The objective of this study was to evaluate the P-gp affinity status of methadone, buprenorphine and diprenorphine to predict P-gp-mediated drug-drug interactions and to determine a better candidate for management of opioid dependence. Two in vitro (P-gp ATPase and monolayer efflux) assays and two in vivo (tissue distribution and antinociceptive evaluation in mdr1a/b (-/-) mice) assays were used. Methadone stimulated the P-gp ATPase activity only at higher concentrations, while verapamil and GF120918 inhibited its efflux (p < 0.05). The brain distribution and antinociceptive activity of methadone were enhanced (p < 0.05) in P-gp knockout mice. Conversely, buprenorphine and diprenorphine were negative in all assays. P-gp can affect the PK/PD of methadone, but not buprenorphine or diprenorphine. Our report is in favor of buprenorphine over methadone for management of opioid dependence. Buprenorphine most likely is not a P-gp substrate and concerns regarding P-gp-mediated drug-drug interaction are not expected.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland, USA.
Hazem E
HE
Hassan
Alan L
AL
Myers
Andrew
A
Coop
Natalie D
ND
Eddington
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000465:Algorithms; D000700:Analgesics / Q000493:pharmacokinetics / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D002047:Buprenorphine / Q000493:pharmacokinetics / Q000494:pharmacology*; D018938:Caco-2 Cells; D002352:Carrier Proteins / Q000235:genetics; D004174:Diprenorphine / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007408:Intestinal Absorption / Q000502:physiology*; D008353:Mannitol / Q000032:analysis / Q000378:metabolism; D008691:Methadone / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D017239:Paclitaxel / Q000032:analysis / Q000378:metabolism; D011487:Protein Conformation; D011930:Reaction Time / Q000187:drug effects; D014018:Tissue Distribution
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000700:Analgesics; D000701:Analgesics, Opioid; D002352:Carrier Proteins; D004174:Diprenorphine; D008353:Mannitol; D002047:Buprenorphine; D000255:Adenosine Triphosphate; C095122:multidrug resistance protein 3; D000251:Adenosine Triphosphatases; C507084:Abcb1b protein, mouse; D017239:Paclitaxel; D008691:Methadone