Enantioselective transport and CYP3A4-mediated metabolism of R/S-verapamil in Caco-2 cell monolayers.

We have evaluated the passive and carrier-mediated intestinal transport and CYP3A4-mediated metabolism of R/S-verapamil with respect to dose dependency and enantioselectivity in modified Caco-2 cells. The present in vitro results were compared to published data from human in vivo and rat in situ jejunal perfusions with R/S-verapamil. Caco-2 cell permeability to enantiomers of verapamil and norverapamil was weakly concentration dependent (2.5-100 microM). While Caco-2 permeability to verapamil was 2.6- to 3.7-fold lower than in the human jejunum, it was 1.4- to 2.3-fold higher than in rats. However, all three models classified R- and S-verapamil as high permeability compounds according to the biopharmaceutical classification system. In accordance with human and rat data, R/S-verapamil was transported to a minor extent by carrier-mediated mechanisms in Caco-2 cells. Neither the passive nor the carrier-mediated permeability was enantioselective in any of the three models. CYP3A4-mediated demethylation to R/S-norverapamil was enantioselective in Caco-2 cells. Apparent V(max) and K(m) values for the conversion of R-verapamil were 3.2 pmol/min/insert and 0.7 microM, respectively, and for S-verapamil, 5.4 pmol/min/insert and 0.6 microM, respectively. The enantioselectivity in the CYP3A4-metabolism observed in Caco-2 cells was in agreement with human data, but not with rat data, indicating that Caco-2 cells better reflect the human small intestine in this regard. However, all three models suggested that intestinal permeability to verapamil is unaffected by CYP3A4-activity. In summary, modified Caco-2 cells and human jejunum were qualitatively related with respect to R-and S-verapamil transport and CYP3A4-metabolism.