THC EFFECTS OF HEPATIC-MICROSOMAL ENZYME INDUCERS ON THE PHARMACOKINETICS OF OUABAIN AFTER PORTAL AND SYSTEMIC ADMINISTRATION TO RATS

The microsomal enzyme inducers 3-methylcholanthrene, phenobarbitone an d pregnenolone-16 alpha-carbonitrile (PCN) are known to affect other a spects of hepato-biliary disposition in addition to metabolism. This s tudy was designed to determine if presystemic elimination of the non-m etabolized xenobiotic ouabain could be altered by these inducers. Male Sprague-Dawley rats were pretreated with inducers or saline for four days. A day later, ouabain (0.5 mg kg(-1)) was administered into eithe r the ileocolic vein (portal administration) or the femoral vein (syst emic administration). Blood and bile samples were collected for up to 90 min after ouabain administration. Biliary excretion rate and cumula tive biliary excretion of ouabain were increased by pretreatment with PCN (75 mg kg(-1)day(-1)) relative to controls. Phenobarbitone pretrea tment (75 mg kg(-1)day(-1)) also increased these parameters, but to a lesser extent than PCN. In contrast, 3-methylcholanthrene pretreatment (20 mg kg(-1)day(-1)) had no effect on biliary excretion. Plasma conc entrations of ouabain were much lower after PCN pretreatment relative to controls, whereas neither phenobarbitone nor 3-methylcholanthrene h ad any effect. Similarly, clearance (both biliary and total) and volum e of distribution were increased by PCN, but not by phenobarbitone or 3-methylcholanthrene pretreatment. Interestingly, the magnitude of bil iary and plasma effects induced by PCN appeared to be comparable wheth er ouabain was administered portally or systemically. Pretreatment of rats with PCN, but not phenobarbitone or 3-methylcholanthrene was show n to increase total clearance of ouabain, mainly via an increase in bi liary clearance. Furthermore, because the enhanced clearance occurs af ter systemic as well as after portal administration of ouabain, a sign ificant change in hepatic presystemic elimination was not detected.