Lack of dextromethorphan interaction with P‐glycoprotein

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