Studies on the Metabolic Fate of Cabergoline (I): Absorption, Distribution, and Excretion after a Single Oral Administration to Rats

The absorption, distribution, and excretion of radioactivity were investigated following a single oral administration of 14C-cabergoline to rats. The protein binding of the drug was also investigated in vivo and in vitro. 1. After oral administration of 14C-cabergoline of a dose of 0.25-1.0 mg/kg to male rats, the plasma level of radioactivity increased and reached the Cmax within 1 hour, which was followed by a biexponential decreased with a t1/2(1-8 hr) of 4.0-6.2 hours and t1/2(24-168 hr) of 33.3-38.4 hours, respectively. Both Cmax and AUC(0-∞) increased approximately in proportion to the dose over the 0.25-1.0 mg/kg dose range. The t1/2(1-8 hr) was increased by food taking. 2. More than 50% of the rad ioactivity was absorbed within 4 hours after injection of 14C-cabergoline into the jejunum or ileum. On the other hand, absorption from the stomach was low. 3. The radioactivity in most tissues after oral dosing of male and female rats with 14C-cabergoline at 0.5 mg/kg reached Cmax at 4 to 8 hours, being higher in liver, lung, and spleen, and lower in the central nervous system of both sexes. And at 168 hours after oral dosing, the radioactivity in testis, hypophysis, harderian gland, brown fat, and trachea decreased to below 30% of each maximum concentration. 4. Within 168 hours after oral dosing with 14C-cabergoline (0.5 mg/kg), the radioactivity excreted in the urine and feces of fasting male rats were 5.6 and 93.1% of dose, respectively; i.e., 98.7% of the radioactivity was excreted. No significant difference was observed between non-fasting, and fasting male rats. 5. Within 48 hours after oral dosing of bile duct-cannulated male, and female rats with 14C-cabergoline (0.5 mg/kg) 33.0 and 25.4%, respectively, of the radioactivity were excreted in the bile. 6. Within 24 hours after intraduodenal injection of the radioactive bile obtained from other rats which had been administered 14C-cabergoline (0.5 mg/kg) orally, 12.3 and 5.0% of the injected radioactivity were excreted in the bile and urine, respectively. 7. The percentage of radioactivity bound to rat serum protein after oral dosing of male and female rats with 14C-cabergoline (0.5 mg/kg) was 62.6-69.2 and 62.4-68.4%, respectively. The percentage of 14C-cabergoline at concentrations of ca. 1.0-15.0 ng /ml bound to rat and human serum protein in vitro was 59.5-70.3 and more than 59.3-65.5%, respectively.