KUNISHIRO K, SHIRAHASE H, MATSUI H, KITAGAWA M, NISHIMURA K, KAKEYA N, KUWAHARA S; Interscience Conference on Antimicrobial Agents and Chemotherapy (43rd: 2003: Chicago, Ill.).

Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2003 Sep 14-17; 43: abstract no. F-534.

Kyoto Pharmaceutical Industries, Ltd., Kyoto, Japan.

BACKGROUND: Meropenem (MEPM) is a parenteral carbapenem with potent activities against clinically important pathogens including penicillin-resistant S. pneumonise, P. aeruginosa and drug-resistant H. influenzae, but its orally active form has not been developed. It is difficult to improve the oral absorption of MEPM using the conventional prodrug method, esterification of carboxylic acid at the C3-position. METHODS: We synthesized a novel series of double prodrugs of MEPM, with ester promoieties at the C3-position and at the N-position on the pyrrolidine ring to improve the oral absorption. RESULTS: Among the prodrugs synthesized, KL-3744 and KL-3758 showed high Cmax after oral dosing at 20 mg/kg as MEPM in male rats (n=4) as follows: 1.2 +/- 0.2 (mean +/- SD) microg/ml for KL-3744 and 0.9 +/- 0.3 microg/ml for KL-3758, respectively. After oral dosing of MEPM, Cmax was only 0.2 microg/ml. In male beagle dogs (n=4), oral absorption of MEPM after administration of KL-3744 and KL-3758 was highly improved and Cmax was about 3 microg/ml at 10 mg/kg (as MEPM). The oral administration of KL-3744 and KL-3758 with coadministration of cilastatin at 40 mg/kg (sc) were both efficacious against murine systemic infection caused by E. coli 11807 with ED[50] of about 0.8 mg/kg/dose. [figure: see text] CONCLUSION: KL-3744 and KL-3758 are promising candidates for the orally active form of MEPM.

Publication Types:

• Meeting Abstracts

Keywords:

• Administration, Oral
• Animals
• Carbapenems
• Cilastatin
• Dogs
• Haemophilus influenzae
• Male
• Penicillins
• Prodrugs
• Rats
• Thienamycins
• blood
• cerebrospinal fluid
• chemical synthesis
• meropenem
• pharmacokinetics

Other ID:

• GWAIDS0026015

UI: 102265639

From Meeting Abstracts