신규 Carbapenem 유도체 CRB 529 및 CRB 550의 생체내 항균효과와 약물동태의 비교

Comparison of in Vivo Antibacterial Activities and Pharmacokinetics of New Carbapenem Derivatives, CRB 529 and CRB 550, in Mice and Rats.

1-beta-Methyl carbapenem-2-substituted pyrrolidine derivatives, CRB 529 and CRB 550, were synthesized as investigational carbapenem derivatives. It has been reported that the in vitro antibacterial activities of the compounds against G(+) and G(-) bacteria were almost the same or more effective than those of imipenem (IPM) and meropenem (MEPM), and also showed better in vivo efficacy than MEPM and imipenem/cilastatin (IPM/CS) against representative G(-) organisms, P. aeruginosa and MRSA organisms, S. aureus. The antibacterial activities, pharmacokinetics and protective efficacy of IPM/CS and CRB 529 and CRB 550 were conducted after subcutaneous or intravenous administration to mice and rats. The pharmacokinetic parameters of CRB 529 and CRB 550 in mice were as follows; the observed maximal serum concentrations (CMAX) following I.V. administration were 87.5 and 101mcg/ml for CRB 529 and CRB 550, respectively, and 63.6mcg/ml for IPM/CS. The half-lives (t1/2) were 14.0 and 12.0 min for CRB 529 and CRB 550, respectively, and 14.8 min for IPM/CS. In rats, CMAX after I.V. administration were 74.0 and 91.8mcg/ml for CRB 529 and CRB 550, respectively, and 41.2mcg/ml for IPM/CS. The tissue levels of CRB 529 and CRB 550 and IPM/CS after I.V. administration at a dose of 20mg/kg decreased by the following order; lung, heart, kidney, liver and spleen for CRB 529, kidney, liver, lung, heart and spleen for CRB 550 and kidney, lung, liver, heart, spleen and brain for IPM/CS. In systemic infection, CRB 529 and CRB 550 showed excellent efficacies against P. aeruginosa and S. aureus (MRSA) at a dose of 5mg/kg. The PD50s were 0.80, 0.36mg/kg for CRB 529 and CRB 550, respectively, and 3.22mg/kg for IPM/CS against P. aeruginosa. The corresponding values against S. aureus (MRSA) were 76.0, 55.3mg/kg for CRB 529 and CRB 550, respectively, and 146mg/kg for IPM/CS. In local infection, the antibacterial activities of CRB 529 and CRB 550 were more effective than those of IPM/CS against intrarenal infection with E. coli and P. aeruginosa and also showed as effective as IPM/CS against respiratory tract infection with E. coli and P. aeruginosa at a dose of 5mg/kg.