Disposition of LY333531, a selective protein kinase C g inhibitor, in the Fischer 344 rat and beagle dog

1. Studies were conducted in the Fischer 344 rat and beagle dog to determine the disposition of LY333531 and its equipotent active des-methyl metabolite, LY338522, both potent and selective inhibitors of the g-isozyme of protein kinase C. 2. Male Fischer 344 rats and female beagle dogs received a single 5-mgkg super(-1) oral dose of super(14)C-LY333531. Urine, faeces, bile and plasma were collected and analysed for super(14)C, LY333531 and LY338522. 3. LY333531 was eliminated primarily in the faeces (91% by 120 h in rat, 90% by 96h in dog). Bile contributed the majority of the radioactivity excreted in the faeces in rat (66% in the cannulated bile duct study) and a variable but significant proportion in dog. 4. Pharmacokinetics following a single 5 mg kg super(-1) oral dose of super(14)C-LY333531 to the male rat produced C sub(max) and AUC sub(0-X) for LY333531 of 14.7 ng ml super(-1) and 60.8ng h ml super(-1), respectively, with a half-life of 2.5 h. LY338522 and total radioactivity showed similar profiles. 5. In the female dog at the same dose, C sub(max) and AUC sub(0-X) of LY333531 were higher, producing 245 - 94 ng ml super(-1) and 1419 - 463ng h ml super(-1), respectively, with a half-life of 5.7 h. 6. The data indicate that the disposition of LY333531 is similar in rat and dog.