Pharmacokinetics, distribution, metabolism and excretion of [H-3]UCN-01 inrats and dogs after intravenous administration

Pur pose: To evaluate the metabolic fate of UCN-01, a signal transduction i nhibitor, blood and plasma concentrations, distribution, metabolism and exc retion were investigated in rats and dogs after intravenous administration of [H-3]UCN-01. Methods: The radioactivity in plasma, blood and tissues was measured after intravenous administration of UCN-01. In addition, the radi oactivity excreted in bile, urine and feces was also determined. Results: T he radioactivity in rat and dog plasma disappeared triphasically with termi nal half-lives of 21.3 and 27.2 h, respectively. The ratios of the blood-to -plasma concentrations ranged from 0.82 to 1.13 in rats and 0.81 to 1.73 in dogs. From 0.5 to 4 h after giving [H-3]UCN-01 to rats, the radioactivity in all tissues except the brain and testes was higher than in plasma. The h ighest concentration was observed in the lungs followed by the liver and ki dneys. The radioactivity was mainly excreted in feces, reaching 96.0% of th e radioactivity dose in rats and 78.4% in dogs up to 168 h after injection. Since the biliary excreted radioactivity was 67.2% over 48 h in bile duct- cannulated rats, most of the radioactivity excreted in feces was from bilia ry radioactivity. There were several metabolites in bile samples, but littl e UCN-01. Conclusions: UCN-01 is mainly eliminated by the liver, and there are high concentrations of radioactivity derived from [H-3]UCN-01 in all ti ssues except the brain and testes.