In vitro P-glycoprotein-mediated transport of (R)-, (S)-, (R,S)-methadone, LAAM and their main metabolites.
Methadone and L-alpha-acetylmethadol (LAAM) are used as treatment for opiate addiction. Using a cellular model, we aimed to determine if methadone, LAAM and their main metabolites are substrates of the human P-glycoprotein transporter (P-gp), which is encoded by the ABCB1 gene, and whether methadone transport exhibits stereoselectivity. Pig kidney epithelial cells (control) and human ABCB1-transfected cells were incubated with methadone, LAAM and their metabolites, and their intra- and extracellular concentrations were measured. The intra- to extracellular ratios of methadone, LAAM and their metabolites were all decreased in ABCB1-transfected cells compared to controls (p < 0.05), thus indicating that they are substrates of P-gp. A weak stereoselectivity in methadone transport was observed towards the (S)-enantiomer. P-gp may therefore affect the pharmacokinetics and pharmacodynamics of methadone and LAAM.
Crettol
Séverine
S
Unité de Biochimie et Psychopharmacologie Clinique, Centre de Neurosciences Psychiatriques, Département de Psychiatrie, Centre Hospitalier Universitaire Vaudois et Université de Lausanne, Hôpital de Cery, Prilly-Lausanne, Suisse.
Digon
Patricia
P
Golay
Kerry Powell
KP
Brawand
Marlyse
M
Eap
Chin B
CB
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000818:Animals; D001692:Biological Transport; D008691:Methadone / Q000493:pharmacokinetics*; D008692:Methadyl Acetate / Q000493:pharmacokinetics*; D011759:Pyrrolidines / Q000493:pharmacokinetics*; D013237:Stereoisomerism; D013552:Swine
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011759:Pyrrolidines; D008692:Methadyl Acetate; D008691:Methadone; C010724:2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine