Abstract
Loracarbef is an oral 1-carba-l-dethiacephalosporin antibiotic structurally related to cefaclor. Like many β-lactam antibiotics, loracar-bef exists in several hydrated crystalline forms. The pH–solubility profile curve for loracarbef monohydrate is U-shaped, resembling those for other zwitterionic cephalosporins. Loracarbef was found to be much more stable in solution than cefaclor. For example, in pH 7.4 phosphate buffer, loracarbef was unexpectedly found to be 130–150 times more stable than cefaclor and 10–12 times more stable than cephalexin, depending on the phosphate concentration. The pH-stability profile is U-shaped, similar to that of other zwitterionic cephalosporins, and shows maximum stability at the isoelectric point. At any given pH, loracarbef is more stable in solution than any other therapeutically useful cephalosporin. Acetate, borate, citrate, and especially phosphate buffers have catalytic effects on the rate of loracarbef hydrolysis.
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REFERENCES
R. N. Guthikonda, L. D. Cama, and B. G. Christensen. Total synthesis of β-lactam antibiotics. VIII. Stereospecific total synthesis of (±)-l-carba-cephalothin. J. Am. Chem. Soc. 96:7584–7585 (1974).
T. Ogasa, H. Saito, Y. Hashimoto, K. Sato, and T. Hirata. Synthesis and biological evaluation of optically active 3-H-l-carbacephem compounds. Chem. Pharm. Bull. 37:315–321 (1989), and references therein.
I. Matsukuma, S. Yoshiiye, K. Mochida, Y. Hashimoto, K. Sato, R. Okachi, and T. Hirata. Synthesis and biological evaluation of 3-chloro-l-carbacephem compounds. Chem. Pharm. Bull. 37:1239–1244 (1989).
L. C. Blaszczak, R. F. Brown, G. K. Cook, W. J. Hornback, J. M. Indelicato, C. L. Jordan, A. S. Katner, M. D. Kinnick, J. H. McDonald III, J. M. Morin, J. E. Munroe, and C. E. Pasini. Comparative reactivity of 1-carba-1-dethiacephalosporins with cephalosporins. J. Med. Chem. 33:1656–1662 (1990).
J. H. Jorgensen, J. S. Redding, and L. A. Mahaer. Influence of storage and susceptibility test conditions on stability and activity of LY163892 and four other cephalosporins. Antimicrob. Agents Chemother. 32:1477–1480 (1988). (Compound LY163892 is loracarbef, 1.)
R. N. Jones and A. L. Barry. Beta-lactamase hydrolysis and inhibition studies of the new 1-carbacephem LY163892. Eur. J. Microbiol. 6:570–571 (1987).
H. Kusmiesz, S. Shelton, O. Brown, S. Manning, and J. D. Nelson. Loracarbef concentrations in middle ear fluid. Antimicrob. Agents Chemother. 34:2030–2031 (1990).
H. Bundgaard. Hydrolysis and intramolecular aminolysis of cephalexin and cephaloglycin in aqueous solution. Arch. Pharm. Chem. Sci. Ed. 4:25–43 (1976).
K. W. B. Austin, A. C. Marshall, and H. Smith. Crystalline modifications of ampicillin. Nature 208:999–1000 (1965).
R. R. Pfeiffer, K. S. Yang, and M. A. Tucker. Crystal pseudopolymorphism of cephaloglycin and cephalexin. J. Pharm. Sci. 59:1809–1814 (1970).
E. Van Heyningen. U.S. Patent 3,531,481 (1972).
R. R. Pfeiffer and K. S. Yang. U.S. Patent 3,655,656 (1970).
D. Bouzard, A. Weber, and J. Sterner. U.S. Patent 4,504,657 (1985).
C. E. Pasini. Eur. Pat. Appl. EP 0 311 366 Al (1989).
T. M. Eckrich and C. E. Pasini. Eur. Pat. Appl. EP 0 369 686 A (1990).
A. T. Tsuji, E. Nakashima, and K. Nishide. Physicochemical properties of amphoteric β-lactam antibiotics. III. Stability, solubility, and dissolution behavior of cefatrizine and cefadroxil as a function of pH. Chem. Pharm. Bull. 31:4057–4069 (1983).
J. M. Indelicato and C. E. Pasini. The acylating potential of γ-lactam antibacterials: Base hydrolysis of bicyclic pyrazolidinones. J. Med. Chem. 31:1227–1230 (1988).
M. Narisaka, J. Nishikawa, F. Watanabe, and Y. Terui. Synthesis and 3′-substituent effects of some 7α-methoxy-l-oxacephems on antibacterial activity and alkaline hydrolysis rates. J. Med. Chem. 30:514–522 (1987).
J. Nishikawa and K. Tori. 3-Substituent effect and 3-methylene substituent effect on the structure-reactivity relationship of 7β-(acylamino)-3-cephem-4-carboxylic acid derivatives studied by carbon-13 and IR spectroscopies. J. Med. Chem. 27:1657–1663 (1984).
D. B. Boyd. Substituent effects in cephalosporins as assessed by molecular orbital calculations, nuclear magnetic resonance, and kinetics. J. Med. Chem. 26:1010–1013 (1983).
A. Schanck, B. Coene, J. M. Dereppe, and M. Van Meerssche. Substituent effect on chemical reactivity of cephalosporins studied by kinetic and 13C NMR. Bull. Soc. Chem. Belg. 92:81–82 (1983).
J. M. Indelicato, A. Dinner, L. R. Peters, and W. L. Wilham. Hydrolysis of 3-chloro-3-cephems. Intramolecular nucleophilic attack in cefaclor. J. Med. Chem. 20:961–963 (1977).
M. Narisada, T. Yoshida, M. Ohtani, K. Ezumi, and M. Takasuka. Synthesis and substituent effects on antibacterial activity, alkaline hydrolysis rates, and infrared absorption frequencies of some cephem analogues related to latamoxef (moxalactam). J. Med. Chem. 26:1577–1579 (1983).
Y. Namiki, T. Tanabe, T. Kobayashi, J. Tanabe, Y. Okimura, S. Koda, and Y. Morimoto. Degradation kinetics and mechanisms of a new cephalosporin, cefixime, in aqueous solution. J. Pharm. Sci. 76:208–214 (1987).
J. M. Indelicato, J. W. Fisher, and C. E. Pasini. Intramolecular nucleophilic amino attack in a monobactam: Synthesis and stability of (2S,3S)-3-[(2R)-2-amino-2-phenylacetamido]-2-methyl-4-oxo-l-azetidinesulfonic acid. J. Pharm. Sci. 75:304–306 (1986).
S. M. Berge, N. L. Henderson, and M. J. Frank. Kinetics and mechanism of degradation of cefotaxime sodium in aqueous solution. J. Pharm. Sci. 72:59–63 (1983).
A. Tsuji, E. Nakashima, Y. Deguchi, K. Nishide, T. Shimizu, S. Horiuchi, K. Ishikawa, and T. Yamana. Degradation kinetics and mechanism of aminocephalosporins in aqueous solution: Cefadroxil. J. Pharm. Sci. 70:1120–1128 (1981).
E. S. Rattie, J. J. Zimmerman, and L. J. Ravin. Degradation kinetics of a new cephalosporin derivative in aqueous solution. J. Pharm. Sci. 68:1369–1374 (1979).
T. Yamana and A. Tsuji. Comparative stability of cephalosporins in aqueous solution: Kinetics and mechanisms of degradation. J. Pharm. Sci. 65:1563 (1976).
J. M. Indelicato, T. T. Norvilas, R. R. Pfeiffer, W. J. Wheeler, and W. L. Wilham. Substituent effects upon the base hydrolysis of penicillins and cephalosporins. Competitive intramolecular nucleophilic amino attack in cephalosporins. J. Med. Chem. 17:523–527 (1974).
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Pasini, C.E., Indelicato, J.M. Pharmaceutical Properties of Loracarbef: The Remarkable Solution Stability of an Oral 1-Carba-l-dethiacephalosporin Antibiotic. Pharm Res 9, 250–254 (1992). https://doi.org/10.1023/A:1018949709797
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DOI: https://doi.org/10.1023/A:1018949709797