AS-924, a novel orally active bifunctional prodrug of ceftizoxime. Synthesis and relationship between physicochemical properties and oral absorption

Ceftizoxime (CZX), a parenteral cephalosporin, has potent and broad antibac terial activity. To improve its oral absorption, we synthesized a series of monofunctional and bifunctional prodrugs of CZX, In rabbits, urinary recov ery after oral administration of CZX was improved by esterification of the carboxyl group at the C-4 position with various lipophilic moieties (monofu nctional prodrugs), and was further increased by introduction of a hydrophi lic L-alanine to the amino group on the thiazole ring at the C-7 position ( bifunctional prodrugs). Least-squares analysis showed good parabolic correl ations between logP and urinary recovery for monofunctional and bifunctiona l prodrugs, respectively, AS-924, a bifunctional prodrug with a pivaloyloxy methyl and L-alanyl moiety had the best balance of lipophilicity and water- solubility for oral absorption among the prodrugs synthesized.