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

Abstract

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 β-isozyme of protein kinase C. 2. Male Fischer 344 rats and female beagle dogs received a single 5-mgkg⁻¹ oral dose of ¹⁴C-LY333531. Urine, faeces, bile and plasma were collected and analysed for ¹⁴C, 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⁻¹ oral dose of ¹⁴C-LY333531 to the male rat produced C_max and AUC_0-∞ for LY333531 of 14.7 ng ml⁻¹ and 60.8ng h ml⁻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_max and AUC_0-∞ of LY333531 were higher, producing 245 ± 94 ng ml⁻¹ and 1419 ± 463ng h ml⁻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.