YAKHAK HOEJI (약학회지)

The Pharmaceutical Society of Korea (대한약학회)
권호 표지

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

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

  • Published : 1995.08.01
Download PDF
⟨ Previous Next ⟩

Abstract

1-$\beta$-Methyl carbapenem-2-substituted pyrroudine 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 inlipeneni/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 wereconducted 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 (C$_{max}$) following I.V. administration were 87.5 and 101 $\mu\textrm{g}$/ml for CRB 529 and CRB 550, respectively, and 63.6 $\mu\textrm{g}$/ml for IPM/CS. The half-lives (t$_{1/2}$) were 14.0 and 12.0 n-dn for CRB 529 and CRB 550, respectively, and 14.8 min for IPM/CS. In rats, $C_{max}$ after I.V. administration were 74.0 and 91.8 $\mu\textrm{g}$/ml for CRB 529 and CRB 550, respectively, and 41.2 $\mu\textrm{g}$/ml for IPM/CS. The tissue levels of CRB 529 and CRB 550 and IPM/CS after I.V. administration at a dose of 20 mg/kg decreased by the following order: lung, heart, kindney, liver and spleen for CRB 529, lddney, 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 5 mg/kg. The PD$_{50s}$ were 0.80, 0.36 mg/kg for CRB 529 and CRB 550, respectively, and 3.22 mg/kg for IPM/CS against P. aeruginosa. The corresponding values against S. aureus (MRSA) were 76.0, 55.3 mg/kg for CRB 529 and CRB 550, respectively, and 146 mg/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 5 mg/kg.

Keywords

References

  1. Chemotherapy v.33 Studies on immunogenecity of imipenem, a carbapenem, and cilastatin sodium, a specific competitive inhibitor of dehydropeptidase-I Maki,E.;Kudo,M.;Yoshida,T.
  2. Chemotherapy v.40 In vitro and in vivo Activities of new carbapenem, meropenem Goto,S.;Miyazaki,S.;Kaneko,Y.
  3. Chemotherapy v.40 Pharmacokinetics of meropenem, a new carbapenem antibiotic, parenterally administrated to laboratory animals Sumita,Y.;Nouda,H.;Tada,E.;Kohzuki,T.;Kato,M.;Okuda,T.;Fukasawa,M.
  4. Antimicrob. Agents Chemother. v.38 Pharmacokinetics of meropenem in patients with intraabdominal infections Bedikian,A.;Okamoto,M.;Nakahiro,R.;Farino,J.;Heseltine,P.;Appleman,M.;Yellin,A.;Berne,T.;Gill,M.
  5. Chemotherapy v.40 Efficacy of meropenem against experimental respiratory tract infection and intrarenal infection in guinea pigs Tanio,T.;Sasaki,T.;Okuda,T.;Fusakawa,M.
  6. The 42th Convention of the Pharmaceutical Society of Korea. abstr. In vitro Antibacterial activities of CRB 529. 535. 538. 545, 550, a new carbapenem antibiotics Kim,J.K.;Min,K.K.;Lee,H.W.;Kim,J.W.
  7. Chemotherapy v.33 Microbiological assay method of imipenem in biological specimens Kesado,T.;Asahi,Y.;Hashizume,T.
  8. Chemotherapy v.40 Assay of meropenem in body fluids and tissues Tomio,T.;Nouda,H.;Kohzuki,T.;Kato,M.;Okuda,T.;Fukasawa,M.
  9. Am. Biotecnol. Lab Bioassay: Large plate methodology Pelletier,R.A.;Nightingale,C.H.
  10. J. Pharmacobio-Dyn. v.8 A pharmacokinetic analysis program (MULTI) for microcomputer Yamaoka,K.;Tanigawara,Y.;Nakagawa,T.;Uno,T.
  11. Antibiotics in laboratory medicine(3rd ed.) Evaluation of new antibiotics in vitro and in experimental animal infections Cleeland,R.;Squires,E.;Lorian,V.(ed.)
  12. Chemotherapy v.33 Effect of imipenem in combination with cilastatin sodium combination on expermental infections in mice Nakamura,K.;Obana,Y.;Nishino,T.;Tanio,T.
  13. Chemotherapy v.33 Toxicological study of imipenem/cilastatin sodium Usui,T.;Kuno,H.;Kuruhara,Y.;Kobayashi,H.
  14. Yakhak Hoeji v.37 In vitro and in vivo Antibacterial activities and pharmacokinetics of 8-fluorociprofloxacin and ciprofloxacin Choi,K.E.;Jung,Y.H.;Kim,J.H.