Tissue distribution and biliary excretion of prostacyclin metabolites in the rat

When tritium labeled prostacyclin (PGI2) or 6-keto PGF1 alpha were injected i.v. into rats, one-third of the dose appeared in the liver after 15 min. Significant levels of radioactivity (8--16%) were also found in the small intestine. These observations plus the prominant fecal excretion of PGI2 radioactivity suggest that PGI2 and/or its metabolites undergo biliary excretion and enterohepatic recirculation. We therefore investigated PGI2 excretion and metabolite composition of the bile in bile duct cannulated rats. After a single bolus i.v. injection of 11-[3H] PGI2 into these rats, an average of 37% of the administered radioactivity was excreted in the bile within 3 hr. A number of metabolites were detected in the bile. The major metabolites were isolated and identified as 2,3-dinor-6-keto-PGF1 alpha and 13,14-dihydro-2,3-dinor-6,15-diketo-PGF1 alpha-glucuronide which each accounted for approximately one-third of the radioactivity in the bile. Other metabolites include 6-keto PGF1 alpha, 13,14-dihydro-2,3-dinor-6,15-diketo-PGF1 alpha, 13,14-dihydro-2,3-dinor-6,15-diketo-20-carboxyl PGF1 alpha and 2,3,4,5,6-pentanor-PGF1 alpha-gamma-lactone. We conclude that the liver plays a pivotal role in the inactivation and disposition of prostacyclin. The predominate metabolic pathways occurring in the liver are probably beta-oxidation and glucuronic acid conjugation.