Abstract
L-749,345 is a carbapenem antibiotic, currently in phase II clinical trials, which possesses a broad antibacterial spectrum and extended half-life. The time courses of levels of the drugs in plasma and urinary recovery were evaluated for L-749,345, imipenem-cilastatin (IPM), and ceftriaxone (CTX) in male rhesus monkeys (Macaca mulatta) and a chimpanzee (Pan troglodytes). The chimpanzee pharmacokinetics was predictive of human results and indicated a compound that was superior to IPM and approached CTX in its ability to persist in the circulation. Levels of binding to protein, in the range of clinically relevant concentrations in serum, are virtually equivalent for L-749,345 and CTX in humans. Results of a crossover bioassay versus those of a high-pressure liquid chromatography assay of 1-g human samples showed that there were no bioactive metabolites of L-749,345. The extended half-life at elimination phase of L-749,345 allows consideration of single daily dosing. In contrast to results with IPM, the improved stability of L-749,345 with respect to hydrolysis by the renal dehydropeptidase I (0.25 times the rate of IPM) results in urinary recovery sufficient for the drug's use as a single agent.
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- Craig W. A. Antimicrobial resistance issues of the future. Diagn Microbiol Infect Dis. 1996 Aug;25(4):213–217. doi: 10.1016/s0732-8893(96)00162-9. [DOI] [PubMed] [Google Scholar]
- Drusano G. L. An overview of the pharmacology of imipenem/cilastatin. J Antimicrob Chemother. 1986 Dec;18 (Suppl E):79–92. doi: 10.1093/jac/18.supplement_e.79. [DOI] [PubMed] [Google Scholar]
- Gold H. S., Moellering R. C., Jr Antimicrobial-drug resistance. N Engl J Med. 1996 Nov 7;335(19):1445–1453. doi: 10.1056/NEJM199611073351907. [DOI] [PubMed] [Google Scholar]
- Holzman M. S. Antimicrobial formulary management: a consultant's perspective. Pharmacotherapy. 1991;11(1 ):14S–18S. [PubMed] [Google Scholar]
- Kropp H., Sundelof J. G., Hajdu R., Kahan F. M. Metabolism of thienamycin and related carbapenem antibiotics by the renal dipeptidase, dehydropeptidase. Antimicrob Agents Chemother. 1982 Jul;22(1):62–70. doi: 10.1128/aac.22.1.62. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Norrby S. R., Björnegård B., Ferber F., Jones K. H. Pharmacokinetics of imipenem in healthy volunteers. J Antimicrob Chemother. 1983 Dec;12 (Suppl 500):109–124. doi: 10.1093/jac/12.suppl_d.109. [DOI] [PubMed] [Google Scholar]
- Patel I. H., Chen S., Parsonnet M., Hackman M. R., Brooks M. A., Konikoff J., Kaplan S. A. Pharmacokinetics of ceftriaxone in humans. Antimicrob Agents Chemother. 1981 Nov;20(5):634–641. doi: 10.1128/aac.20.5.634. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Roark M. K., Reed W. E., Jr Econotherapeutics. Diagn Microbiol Infect Dis. 1995 May-Jun;22(1-2):209–217. doi: 10.1016/0732-8893(95)00078-o. [DOI] [PubMed] [Google Scholar]
- Sundelof J. G., Thompson R., White K. M., Sasor M. W., Cama L., Kropp H. Pharmacokinetics in nonhuman primates of a prototype carbapenem active against methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 1996 Mar;40(3):795–798. doi: 10.1128/aac.40.3.795. [DOI] [PMC free article] [PubMed] [Google Scholar]