Lack of dextromethorphan interaction with P-glycoprotein

Abstract

Background The analgesic anti-NMDA effect of dextromethorphan (DEM) might result mainly from a central action of unchanged DEM rather than from its more active metabolite dextrorphan (DOR). This could be related to a weaker interaction of DEM with the efflux drug transporter P-glycoprotein (P-gP) as compared with that of DOR. Aim We studied the involvement of P-gP in the transepithelial transport of DEM and DOR. Methods We used the human intestinal Caco-2 cell monolayer model. Bidirectional transport of 1, 5 and 10 μM DEM across the Caco-2 monolayers was investigated in the presence and absence of the P-gP inhibitor verapamil (100μM). DEM quantitation was performed using HPLC. Results We found that: i) DEM showed no statistically significant differential transport rates between the basolateral-to-apical (B-A) and apical-to-basolateral (A-B) directions at 5 and 10μM (apparent permeability coefficient Papp: 17 vs 16.10−6 and 29 vs 31.10−6 cm/s respectively). However, at 1μM, the rate of transport A-B was greater (Papp: 5 vs 7.10−6 cm/s); ii) B-A transport of DEM was not affected by verapamil (Papp: 5 vs 5.10−6; 17 vs 16.10−6 and 29 vs 30.10−6 cm/s); iii) The transepithelial transport of DEM was concentration-dependant. Conclusion The data indicate that DEM is not a P-glycoprotein substrate at therapeutic concentrations and that the mechanism of diffusion is passive. Clinical Pharmacology & Therapeutics (2005) 77, P10–P10; doi: 10.1016/j.clpt.2004.11.039