4 research outputs found
Uptake/Efflux Transport of Tramadol Enantiomers and O-Desmethyl-Tramadol: Focus on P-Glycoprotein
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
Rôle de la P-glycoprotéine dans le transport d'analgésiques et de neuromodulateurs d'action centrale : validation et application du modèle Caco-2
Lors du développement préclinique des médicaments, les processus de sélection d'une molécule exigent l'étude de son profil pharmacocinétique, déterminé par les caractéristiques d'absorption, distribution, métabolisme et élimination (ADME). Dans ce cadre, diverses méthodes d'exploration systématique ont été développées ces dernières années dans le but d'évaluer rapidement et à grande échelle les propriétés biopharmaceutiques d'un composé, notamment sa solubilité, sa perméabilité intestinale, son métabolisme par certains isoenzymes tels que les cytochromes P450 (CYP450) et plus récemment, son potentiel d'interaction avec des transporteurs d'efflux et d'influx
Lack of interaction of the NMDA receptor antagonists dextromethorphan and dextrorphan with P-glycoprotein
The anti-N-methyl-D-aspartate (NMDA) effect of dextromethorphan (DEM) seems to be mainly related to the unchanged drug rather than to its more potent metabolite dextrorphan (DOR). The aim of our study was to assess the involvement of P-glycoprotein (P-gp) and pH conditions in the transmembranal transport of these two NMDA antagonists, using a human in vitro Caco-2 cell monolayer model. Transmission electron microscopy, transepithelial electrical resistance, [(3)H]-mannitol permeability, Western blot analysis and the bidirectional transport of the positive controls, rhodamine and digoxine were used to confirm model's integrity and validity. The bidirectional transport of DEM and DOR (1 to 100microM) across the monolayers was investigated in the presence and absence of the P-gp inhibitor cyclosporine A (10microM) at two pH conditions (pH 6.8/7.7-pH 7.4/7.4) and assessed with the specific and more potent P-gp inhibitor GF120918 (4microM). Analytical quantification was achieved using high performance liquid chromatography. At a pH gradient, DEM and DOR were subject to a significant active efflux transport (Papp(B-A) > 2-3x Papp(A-B); p<0.01). However, neither the influx nor the efflux was affected by P-gp inhibitors. At physiological pH, we observed no more efflux of the drugs and no influence of the inhibitors. In conclusion, dextromethorphan and dextrorphan are not P-gp substrates. However, pH-mediated efflux mechanisms seem to be involved in limiting DEM gastrointestinal absorption. The preferential anti-NMDA central effect of DEM appears to be P-gp independent
P-glycoprotein is not involved in the differential oral potency of naloxone and naltrexone
The poor oral bioavailability of the opioid receptor antagonist naloxone (NA) when compared with naltrexone (NX) may be related to a greater interaction of naloxone with the efflux drug transporter P-glycoprotein (P-gp). We studied the involvement of P-gp in the transepithelial transport of the two opioid receptor antagonists, using a validated human in vitro Caco-2 cell monolayer model. The bidirectional transport of NA and NX (1, 50 and 100 microm) across the monolayers was investigated in the presence and absence of the specific P-gp inhibitor GF120918 (4 microm). NA and NX showed equal transport rates between the apical-to-basolateral (A-B) and the basolateral-to-apical (B-A) directions and neither the influx nor the efflux transport was affected by the P-gp inhibitor (P > 0.05). In conclusion, NA and NX are not P-gp substrates. The differential oral bioavailability of the two opioid antagonists is P-gp independent