Repeated oral rifampicin decreases the jejunal permeability of R/S-verapamil in rats

The main purpose of this rat study was to investigate the effect of rifampi cin on the effective permeability (P-eff) of R/S-verapamil in the rat jejun um. In addition the effect on metabolism of RIS-verapamil to R/S-norverapam il was examined. In situ single-pass perfusions of the rat jejunum were per formed in animals pretreated with oral rifampicin (250 mg/kg/day) or saline (control) over various time periods (1, 4, 7, and 14 days). The jejunal P- eff of each of the enantiomers of verapamil and D-glucose was estimated. Th e appearance ratios of the CYP3A-formed metabolites R- and S-norverapamil w ere also estimated in the outlet jejunal perfusate, The jejunal P-eff of bo th R- and S-verapamil decreased as an effect of the oral pretreatment with rifampicin. The appearance of R- and S-norverapamil in the jejunum was also affected by the oral pretreatment with rifampicin, with increasing concent rations of R/S-norverapamil being evident after 14 days of rifampicin pretr eatment. There was no stereoselectivity in either the P-eff of R- and S-ver apamil or the metabolic appearance of R- and S-nonrerapamil, Treatment with oral rifampicin decreased the P-eff of R/S-verapamil, which is in accordan ce with an induction of P-glycoprotein activity in the apical enterocyte me mbrane, The increase in appearance of R/S-norverapamil in jejunum is in acc ordance with an induction of CYP3A metabolism in the rat.