title: Disposition of LY333531, a selective protein kinase C beta 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 beta-isozyme of protein kinase C. 2. Male Fischer 344 rats and female beagle dogs received a single 5-mg kg(-1) oral dose of (14)C-LY333531. Urine, faeces, bile and plasma were collected and analysed for (14)C, LY333531 and LY338522. 3. LY333531 was eliminated primarily in the faeces (91% by 120 h in rat, 90% by 96 h 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 (14)C-LY333531 to the male rat produced C(max) and AUC(0-infinity ) for LY333531 of 14.7 ng ml(-1) and 60.8 ng 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-infinity ) of LY333531 were higher, producing 245 +/- 94 ng ml(-1) and 1419 +/- 463 ng 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.
authors.affiliation: Lilly Research Laboratories, Division of Eli Lilly and Co, Lilly Corporate Center, Indianapolis, IN 46285, USA. burkey_jennifer_l@lilly.com
authors.forename: J L
authors.initials: JL
authors.lastname: Burkey
authors.forename: K M
authors.initials: KM
authors.lastname: Campanale
authors.forename: D D
authors.initials: DD
authors.lastname: O'Bannon
authors.forename: J W
authors.initials: JW
authors.lastname: Cramer
authors.forename: N A
authors.initials: NA
authors.lastname: Farid
mesh_terms: D000818:Animals; D019540:Area Under Curve; D004285:Dogs; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D005260:Female; D007211:Indoles / Q000493:pharmacokinetics*; D008297:Male; D008301:Maleimides / Q000493:pharmacokinetics*; D008956:Models, Chemical; D020033:Protein Isoforms; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051381:Rats; D011916:Rats, Inbred F344; D013045:Species Specificity; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; C474461:LY 338522; D008301:Maleimides; D020033:Protein Isoforms; C099154:ruboxistaurin; D011493:Protein Kinase C