title: Uptake/efflux transport of tramadol enantiomers and O-desmethyl-tramadol: focus on P-glycoprotein.
abstract: The analgesic effect of tramadol (TMD) results from the monoaminergic effect of its two enantiomers, (+)-TMD and (-)-TMD as well as its opioid metabolite (+)-O-desmethyl-tramadol (M1). P-glycoprotein (P-gp) might be of importance in the analgesic and tolerability profile variability of TMD. Our study investigated the involvement of P-gp in the transepithelial transport of (+)-TMD, (-)-TMD and M1, using a Caco-2 cell monolayer model. The bidirectional transport of racemic TMD and M1 (1-100 microM) across the monolayers was investigated at two pH conditions (pH 6.8/7.4 and 7.4/7.4) in the presence and absence of P-gp inhibitor cyclosporine A (10 microM) and assessed with the more potent and specific P-gp inhibitor GF120918 (4 microM). Analytical quantification was performed by liquid chromatography coupled to the fluorescence detector. A net secretion of (+)-TMD, (-)-TMD and M1 was observed when a pH gradient was applied (TR: P(app)(B - A)/P(app)(A - B): 1.8-2.7; P < 0.05). However, the bidirectional transport of all compounds was equal in the non-gradient system. In the presence of P-gp inhibitors, a slight but significant increase of secretory flux was observed (up to 26%; P < 0.05) at both pH conditions. In conclusion, (+)-TMD, (-)-TMD and M1 are not P-gp substrates. However, proton-based efflux pumps may be involved in limiting the gastrointestinal absorption of TMD enantiomers as well as enhancing TMD enantiomers and M1 renal excretion. A possible involvement of uptake carriers in the transepithelial transport of TMD enantiomers and M1 is suggested.
authors.affiliation: Department of Anaesthesiology, Clinical Pharmacology and Toxicology and Multidisciplinary Pain Center, Pharmacology and Intensive care, Geneva University Hospitals, Faculty of Medicine, University of Geneva, CH-1211 Geneva 14, Switzerland.
authors.forename: Mouna
authors.initials: M
authors.lastname: Kanaan
authors.forename: Youssef
authors.initials: Y
authors.lastname: Daali
authors.forename: Pierre
authors.initials: P
authors.lastname: Dayer
authors.forename: Jules
authors.initials: J
authors.lastname: Desmeules
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000701:Analgesics, Opioid / Q000493:pharmacokinetics*; D001692:Biological Transport; D018938:Caco-2 Cells; D017097:Electric Impedance; D006801:Humans; D006863:Hydrogen-Ion Concentration; D013237:Stereoisomerism; D014147:Tramadol / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000701:Analgesics, Opioid; C080580:O-demethyltramadol; D014147:Tramadol