JEJUNAL-ABSORPTION AND METABOLISM OF R S-VERAPAMIL IN HUMANS/

Purpose. The purpose of this human intestinal perfusion study was to i nvestigate the transport and metabolism of RIS-verapamil in the human jejunum (in vivo). Methods. A regional single-pass perfusion of the je junum was performed using a Loc-I-Gut(R) perfusion tube in 12 healthy volunteers. Each perfusion lasted for 200 min and was divided into two periods each of 100 min. The inlet concentrations of verapamil were 4 .0 and 40 mg/l in period one and two, respectively.Results. The effect ive jejunal permeability (Peff) of both R- and S-verapamil increased ( p < 0.05) when the inlet concentration was increased consistent with s aturation of an efflux mechanism. However, both R- and S-verapamil had high intestinal Peff, consistent with complete absorption. The Peff o f antipyrine also increased, but there was no difference in the Peff f or D-glucose in the two periods. The appearance of R/S-norverapamil in the intestinal perfusate leaving the jejunal segment was non-linear, presumably due to saturation of the CYP3A4 metabolism. Conclusions. Th e increased Peff in parallel with increased entering drug concentratio n is most likely due to saturable efflux by P-glycoprotein(s) in the h uman intestine.