AS-924, a novel, orally active, bifunctional prodrug of ceftizoxime: physicochemical properties, oral absorption in animals, and antibacterial activity

Citation
N. Mori et al., AS-924, a novel, orally active, bifunctional prodrug of ceftizoxime: physicochemical properties, oral absorption in animals, and antibacterial activity, INT J ANT A, 18(5), 2001, pp. 451-461
Citations number
9
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Microbiology
Journal title
INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS
ISSN journal
0924-8579 → ACNP
Volume
18
Issue
5
Year of publication
2001
Pages
451 - 461
Database
ISI
SICI code
0924-8579(200111)18:5<451:AANOAB>2.0.ZU;2-1
Abstract
AS-924 is an oral prodrug of the antibiotic ceftizoxime (CTIZ), a parentera l use cephalosporin. This novel prodrug, produced by esterifying CTIZ with a lipophilic pivaloyloxymethyl (POM) group and introducing a water soluble L-alanyl group, is expected to increase the bioavailability and thereby, au gment the antibacterial activity of CTIZ in vivo compared with existing pro drugs. To study the effect of the L-alanyl group in AS-924 on its bioavaila bility, the plasma concentration profiles of CTIZ in dogs were examined fol lowing the dosing of AS-924 and CTIZ-POM, in powder form, after pretreatmen t with the antacid ranitidine, and following the dosing of AS-924 after pre treatment with a gastrointestinal motility stimulant metoclopramide or supp ressant scopolamine butylbromide. The absorption rate of AS-924 was constan t under these different conditions due to its unique balance of lipophilici ty and water solubility. CTIZ is as antibacterially active as pre-existing oral cephalosporins against Gram-positive clinical isolates, while being mo re active against all Gram-negative isolates-particularly Enterobacteriacea e and Haemophilus influenzae. A simulation model for the eradication profil e of bacteria in computer programmed pharmacokinetic (PK) system was carrie d out to study the antibacterial action of CTIZ in human. CTIZ was proven t o eradicate Streptococcus pneumoniae and H. influenzae effectively, while c efpodoxime (CPOD), the active moiety of CPOD proxetil, eradicated S. pneumo niae, but not H. influenzae. These results confirm that, AS-924 is a potent oral antibiotic and would be expected to be clinically effective and effic ient. (C) 2001 Published by Elsevier Science B.V. and International Society of Chemotherapy.