FRIIS JM, STEENWYK RC, WILLIAMS MG, PALANDRA J, HOSLEY JD, JENSEN JL, SMITH DP, BIERMACHER JJ, PERRICONE SV, STELZER LS, NIDY EG, HESTER JB, ADAMS WJ; Interscience Conference on Antimicrobial Agents and Chemotherapy (41st : 2001 : Chicago, Ill.).
Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2001 Dec 16-19; 41: abstract no. F-1039a.
Pharmacia Corporation, Kalamazoo, MI
BACKGROUND: As part of a comprehensive examination of the structure activity relationships of the oxazolidinone class of antibacterials, oxazolidinone thioamide analogs were synthesized. The thioamide PNU-173995 had improved activity relative to the corresponding carboxamide (PNU-100592). Early in our investigations of PNU-173995 unexpected species differences in the pharmacokinetics of the compound were discovered. We report here our investigations of the pharmacokinetics and metabolism of PNU-173995 in the rat, dog and monkey. METHODS: Pharmacokinetic studies were done using male animals in parallel design studies. In vitro studies were done using rat, dog, monkey and human liver microsomes. RESULTS: In rats, PNU-173995 had moderate clearance and good oral bioavailability (64%). The major pathway of metabolism in rats was via S-oxidation to form PNU-100592. In monkeys, PNU-173995 had moderate clearance and considerably lower oral bioavailability (30+/-11%) than in the rat. The predominant pathway of metabolism in the monkey was des-glycoloylation and not S-oxidation, with substantial systemic concentrations of the des-glycoloyl metabolite observed. In dogs, PNU-173995 had high clearance and low oral bioavailability (38+/-19%). Little if any des-glycoloylation occurred in the dog. High systemic concentrations of S-oxide and eperezolid metabolites were observed in the dog as compared to the monkey and rat. CONCLUSION: S-Oxidation of PNU-173995 increased in the rank order monkey < rat << dog and des-glycoloylation increased in the rank order dog < rat << monkey. There was good agreement in the in vitro and in vivo results.
Publication Types:
Keywords:
- Animals
- Biological Availability
- Dogs
- Haplorhini
- Humans
- In Vitro
- Male
- Microsomes, Liver
- Muridae
- Oxazoles
- Phenylurea Compounds
- Rats
- Rats, Sprague-Dawley
- Thioamides
- metabolism
- pharmacokinetics
- pyriminil
Other ID:
UI: 102270036
From Meeting Abstracts