Metabolic Fate of YM992. Absorption, Distribution, Excretion and Metabolic Fingerprinting after a Single Oral Administration of 14C-YM992 to Rats.

Abstract

The absorption, distribution, metabolism and excretion of radioactivity were investigated after a single oral administration of 30 mg/kg of 14C-YM992 to rats. 1. Blood and plasma radioactivity levels reached the Cmax at 30 min after administration, and then decreased bi-phasically with terminal half-lives (t1/2) of 7.2 and 5.5 hr, respectively. Plasma unchanged drug levels reached the Cmax 15 min after dosing, and then decreased bi-phasically with a t1/2 of 1.2 hr. The ratios of the unchanged drug to total radioactivity level in the plasma were 1.6% and 4.1% at 5 and 15 min after dosing, respectively, and subsequently decreased to 0.1% at 8 hr after dosing. 2. 14C-YM992 was well absorbed from the duodenum to the colon but not stomach. 3. Radioactivity was distributed quickly into various tissues, showing a peak level within 1 hr after dosing in most tissues. Radioactivity levels (excluding the gastrointestinal tract) at 1 hr after dosing were highest in the liver, followed by the kidney, lung, adrenal, bone marrow, spleen, submandibular gland, and pancreas. Radioactivity disappeared relatively rapidly from most tissues, reflecting a decrease in the plasma concentration. The ratio of the unchanged drug to total radioactivity level in the cerebrum was 62.8% at 15 min after dosing, and subsequently decreased time-dependently to 33.3% at 24 hr after dosing. 4. Within 168 hr after dosing, 61.3% and 37.7% of the dosed radioactivity were excreted in the urine and feces, respectively. In bile-duct cannulated rats, 58.0 % and 39.4% of the dosed radioactivity were excreted within 72 hr in the bile and urine, respectively. At least 70.6% of the radioactivity excreted in bile was reabsorbed. 5. At least 18 peaks of radioactivity were observed in the radio-chromatogram of plasma at 1 hr after dosing, and at least 10 peaks in the radio-chromatograms of urine and bile collected for 6 hr after dosing. Little or trace amount of unchanged drug was observed in these samples. In the radio-chromatogram of cerebrum at 1 hr after dosing, at least 9 peaks of radioactivity were observed, and the main peak corresponded to the unchanged drug.