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 rifampicin on the effective permeability (P(eff)) of R/S-verapamil in the rat jejunum. In addition the effect on metabolism of R/S-verapamil to R/S-norverapamil was examined. In situ single-pass perfusions of the rat jejunum were performed 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. The appearance ratios of the CYP3A-formed metabolites R- and S-norverapamil were also estimated in the outlet jejunal perfusate. The jejunal P(eff) of both 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 concentrations of R/S-norverapamil being evident after 14 days of rifampicin pretreatment. There was no stereoselectivity in either the P(eff) of R- and S-verapamil or the metabolic appearance of R- and S-norverapamil. Treatment with oral rifampicin decreased the P(eff) of R/S-verapamil, which is in accordance with an induction of P-glycoprotein activity in the apical enterocyte membrane. The increase in appearance of R/S-norverapamil in jejunum is in accordance with an induction of CYP3A metabolism in the rat.
Sandström
R
R
Department of Pharmacy, Uppsala University, Uppsala, Sweden.
Lennernäs
H
H
D000465:Algorithms; D000818:Animals; D000904:Antibiotics, Antitubercular / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics*; D005947:Glucose / Q000378:metabolism; D007408:Intestinal Absorption / Q000187:drug effects*; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D012293:Rifampin / Q000494:pharmacology*; D013237:Stereoisomerism; D014700:Verapamil / Q000031:analogs & derivatives / Q000493:pharmacokinetics*
D000904:Antibiotics, Antitubercular; D002121:Calcium Channel Blockers; C016904:norverapamil; D014700:Verapamil; D005947:Glucose; D012293:Rifampin