ABSTRACT
BACKGROUND AND AIM: Olmesartan (RNH-6270) is a newly developed anigotensin II receptor antagonist, and has been reported to be excreted into feces. To examine the mechanism of the biliary excretion of olmesartan, we studied its biliary excretion in rats. METHODS: The biliary excretion of olmesartan in Eisai hyperbilirubinemic rats (EHBR), a multidrug resistance protein 2-deficient rat, was compared with control rats, and the effect of organic anions and cation and bile acids on the biliary excretion of olmesartan was studied in control rats. RESULTS: The biliary excretion of olmesartan was markedly delayed in EHBR. The biliary excretion of olmesartan was inhibited by sulfobromophthalein, cefpiramide and pravastatin, but was not inhibited by taurocholate or tauroursodeoxycholate. Vinblastine inhibited and phenothiazine treatment increased the biliary excretion of olmesartan. CONCLUSIONS: These findings suggest that olmesartan is excreted into the bile mainly by multidrug resistance protein 2 and partly by P-glycoprotein.
Subject(s)
Angiotensin II Type 1 Receptor Blockers/pharmacokinetics , Common Bile Duct/metabolism , Imidazoles/pharmacokinetics , Tetrazoles/pharmacokinetics , ATP-Binding Cassette Transporters/physiology , Animals , Cephalosporins/pharmacology , Common Bile Duct/drug effects , Male , Olmesartan Medoxomil , Phenothiazines/pharmacology , Pravastatin/pharmacology , Rats , Rats, Mutant Strains , Rats, Sprague-Dawley , Sulfobromophthalein/pharmacology , Taurochenodeoxycholic Acid/pharmacology , Taurocholic Acid/pharmacology , Vinblastine/pharmacologyABSTRACT
BACKGROUND/PURPOSE: In patients with complete bile duct obstruction, the only pathway for the elimination of cholephilic compounds is through the urine. Although changes in various transporters in the liver and kidney in cholestasis have been elucidated, little is known about how effectively the elimination of these compounds is compensated for by urinary excretion. METHODS: In the present study, the urinary excretion of pravastatin and temocapril was studied in bile-duct-ligated rats (BDLR) for 3 days and in Eisai hyperbilirubinemic rats (EHBR). After urinary bladder cannulation, radiolabeled pravastatin and temocapril were injected intravenously. Urine samples were collected every 1 h for 4 h, and the radioactivity was counted. RESULTS: Urinary excretion of pravastatin was markedly increased in BDLR (85.9% of the dose after 4 h) and moderately increased in EHBR (35.9% of the dose after 4 h) compared with that in control rats (5.5% of the dose after 4 h). Similar but less prominent differences were observed with temocapril after it was administered (50.7%, 38.2%, and 22.0% of the dose after 4 h in BDLR, EHBR, and the controls, respectively). CONCLUSIONS: The absence of biliary excretion of anionic drugs was compensated for by urinary excretion in BDLR and EHBR, and the compensation was more efficient with pravastatin than with temocapril. In patients with complete bile duct obstruction, the only pathway for the elimination of cholephilic compounds is through the urine. Although changes in various transporters in the liver and kidney in cholestasis have been elucidated, little is known about how effectively the elimination of these compounds is compensated for by urinary excretion.
