Abstract
In order to clarify the metabolic fate of MCI-186 in rats, blood and plasma levels, distribution, metabolism and excretion were investigated after a single intravenous administration of 14C-MCI-186 to male and female rats.
1) After intravenous administration of 14C-MCI-186 (0.3, 2, 5.2 mg/kg), blood levels of radioactivity decreased relatively rapidly, and the areas under the concentration time curves (AUC0→∞) correlated well with doses (r=0.987).
2) Plasm a levels of radioactivity and the unchanged MCI-186 decreased rapidly and biphasically after intravenous administration of 14C-MCI-186 (2 mg/kg). In plasma, sulfate of MCI-186, unchanged MCI-186 and glucuronide of MCI-186 were present in higher levels and their AUC0→∞ accounted for 30 ?? 33%, 13 ?? 15% and 6 % of the AUC0→∞ of plasma radioactivities, respectively.
3) Distribution of radioactivity to tissues was rapid, and disappearance of radioactivity was also rapid except from the blood vessel (aorta). Disappearance of radioactivity from blood vessel was very delayed. And sex difference was observed in these disappearance, that is, in female rats radioactivities in tissues decreased more rapidly than in male rats. Concentrations of radioactivity in brain at 5 min after administration were low corresponding to 1/16 ?? 1/18 of the concentrations in plasma, and site specific distribution in brain was not observed. Most of radioactivity in brain consisted with unchanged MCI-186, and most of radioactivity in kidney consisted of sulfate of MCI-186.
4) Excretion of radioactivity was rapid and complete in both male and female rats. Eighty six to 92% of the dosed radioactivity was excreted to urine, therefore main excretion route was urinary excretion. Biliary excretion was 4.6% of the dose and it is possible that most of it was subjected to entero-hepatic circulation.
