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Uptake/Efflux Transport of Tramadol Enantiomers and O ‐Desmethyl‐Tramadol: Focus on P ‐Glycoprotein
Author(s) -
Kanaan Mouna,
Daali Youssef,
Dayer Pierre,
Desmeules Jules
Publication year - 2009
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/j.1742-7843.2009.00428.x
Subject(s) - tramadol , chemistry , enantiomer , pharmacology , p glycoprotein , efflux , analgesic , desmethyl , metabolite , tramadol hydrochloride , biochemistry , medicine , stereochemistry , multiple drug resistance , antibiotics
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 µM) 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 µM) and assessed with the more potent and specific P ‐gp inhibitor GF120918 (4 µM). 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.