DISPOSITION AND METABOLISM OF [¹⁴C] AT-2266

II. REPEATED ADMINISTRATION

Abstract

Disposition and metabolism of [¹⁴C] AT-2266 were studied after 7 oral consecutive daily dosings in rats.
1. Blood levels of [¹⁴C] AT-2266 radioactivity after the initial and final administration were essentially similar to each other. Levels 1 hr after each dosing were around 2.5μg eq./ml. Unchanged [¹⁴C] AT-2266 accounted for about 60% of total radioactivity in plasma 1 hr after the last administration.
2. Tissue levels of [¹⁴C] AT-2266 radioactivity 1 hr after the last administration were the highest in the digestive tract, liver, kidney, seminal vesicle and prostate among organs examined (the latter two, however, being mostly attributed to artifact caused by urine contamination after sacrifice of animals for autopsy). Most of tissue levels were higher than blood level but were lower in such tissues as testicle and fat. The brain level was under reliable limit of detection. Unchanged [¹⁴C] AT-2266 accounted for> 70% of total radioactivity in the liver and kidney, and >90%, in lung and heart. Levels in most tissues were not detected or<1μg eq./g 24 hr after the last administration. Autoradiographic findings agreed with above radiometric findings.
3. About 30 and 60% of dosed radioactivity were excreted in urine and feces, respectively, during and after repeated administration.
4. About 67% of urinary radioactivity were derived from the unchanged [¹⁴C] AT-2266 and about 21%, its glucuronide.
5. Disposition and metabolism of [¹⁴C] AT-2266 after repeated administration were thus essentially similar to those after single administration reported previously. The results suggest that none of any significant accumulation of [¹⁴C] AT-2266 radioactivity in tissues, any delay in excretion and metabolic alteration occurs even after repeated administration, implying its safety in long term administration.