The absence of stereo selective P-glycoprotein-mediated transport of R/S-verapamil across the rat jejunum

We have studied the potential stereoselective transport and metabolism of R /S-verapamil in rat jejunum, in-situ. A regional single-pass perfusion of the rat jejunum was performed on 24 rat s in six separate groups. The effective permeability (P-eff) was assessed f or three different concentrations of verapamil, 4, 40 and 400 mg L-1 The P- eff of each enantiomer was also determined at 400 mg L-1 when chlorpromazin e (10 mM) was added to the perfusion solution. Two other groups of rats rec eived RIS-verapamil as an intravenous infusion and the intestinal secretion and metabolism were studied by simultaneously perfusing the jejunum with a control or with chlorpromazine (10 mM) added. The concentrations in the ou tlet perfusate of each enantiomer of verapamil and norverapamil were assaye d with HPLC. R/S-Verapamil is a high permeability drug in the proximal rat small intestine throughout the luminal concentration range studied and comp lete intestinal absorption was expected. There was an increase of P-eff fro m 0.42 x 10(-4) cm s(-1) to 0.80 x 10(-4) cm s(-1) (P < 0.05) at concentrat ions from 4 to 400 mg L-1, respectively. The observed concentration-depende nt jejunal P-eff and fraction absorbed (P < 0.05) of RIS-verapamil is consi stent with the saturation of an efflux mechanism. When chlorpromazine (a P- glycoprotein inhibitor/substrate) was added the jejunal P-eff increased to 1.47 x 10(-4) cm s(-1). There was no difference between the P-eff of the tw o enantiomers in any of these experiments. The efflux of RIS-norverapamil i nto the rat jejunum was high after intravenous administration of RIS-verapa mil, suggesting extensive metabolism in the enterocyte. In conclusion, both RIS-verapamil enantiomers are P-glycoprotein substrates , but there is no stereoselective transport of RIS-verapamil in the rat jej unum. The results also suggests that RIS-norverapamil is formed inside the enterocytes.