title: AS-924, a novel orally active bifunctional prodrug of ceftizoxime. Synthesis and relationship between physicochemical properties and oral absorption.
abstract: Ceftizoxime (CZX), a parenteral cephalosporin, has potent and broad antibacterial activity. To improve its oral absorption, we synthesized a series of monofunctional and bifunctional prodrugs of CZX. In rabbits, urinary recovery after oral administration of CZX was improved by esterification of the carboxyl group at the C-4 position with various lipophilic moieties (monofunctional prodrugs), and was further increased by introduction of a hydrophilic L-alanine to the amino group on the thiazole ring at the C-7 position (bifunctional prodrugs). Least-squares analysis showed good parabolic correlations between log P and urinary recovery for monofunctional and bifunctional prodrugs, respectively. AS-924, a bifunctional prodrug with a pivaloyloxymethyl and L-alanyl moiety had the best balance of lipophilicity and water-solubility for oral absorption among the prodrugs synthesized.
authors.affiliation: Research Laboratories, Kyoto Pharmaceutical Industries, Ltd., Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kasai
authors.forename: S
authors.initials: S
authors.lastname: Hatano
authors.forename: M
authors.initials: M
authors.lastname: Kitagawa
authors.forename: A
authors.initials: A
authors.lastname: Yoshimi
authors.forename: K
authors.initials: K
authors.lastname: Nishimura
authors.forename: N
authors.initials: N
authors.lastname: Mori
authors.forename: A
authors.initials: A
authors.lastname: Sakai
authors.forename: T
authors.initials: T
authors.lastname: Sugihara
mesh_terms: D000284:Administration, Oral; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D019540:Area Under Curve; D015296:Ceftizoxime / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D002511:Cephalosporins / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004285:Dogs; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D008297:Male; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011817:Rabbits; D012995:Solubility
chemical_list: D000596:Amino Acids; D002511:Cephalosporins; D011355:Prodrugs; C121334:ceftizoxime alapivoxil; D015296:Ceftizoxime