Prodrugs pp 1185-1194 | Cite as

Case Study: Cefditoren Pivoxil: An Oral Prodrug of Cefditoren

  • Tarra Fuchs
Part of the Biotechnology: Pharmaceutical Aspects book series (PHARMASP, volume V)


There is a continual need for new broad-spectrum antibiotics and, with this in mind, Sakagami and coworkers developed cefditoren pivoxil (Spectracef®) as an orally available prodrug of cefditoren (1990). Cefditoren has a 2-aminothiazole methoxime ring that imparts gram-negative activity (Balbisi, 2002) and a methylthiazole-substituted vinyl group at C-3 that maintains gram-positive activity (Sakagami et al.,1990). However, the hydrophilic carboxyl group of the parent drug makes cefditoren orally inactive due to poor permeation across the intestinal mucosa (Kees and Grobecker, 1995; Stoeckel et al., 1995). Esterfication of the polar carboxyl group increases lipophilicity and allows intestinal absorption to occur (Kees and Grobecker, 1995). That is, cefditoren pivaloyl methyl ester is not biologically active, but after absorption esterases readily hydrolyze the prodrug to the biologically active cefditoren (von Daehne et al., 1970; Li et al., 1997; Brass et al., 2003).


Moraxella Catarrhalis Sodium Tripolyphosphate Oral Cephalosporin Cefetamet Pivoxil Pivalic Acid 


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  1. Anon. Spectracef® [Package Insert]. Stampford, CT: Purdue Pharmaceutical Products LP. 2003Google Scholar
  2. Balbisi EA. Cefditoren, a New Aminothiazolyl Cephalosporin. Pharmacotherapy 2002; 22:1278–1292PubMedCrossRefGoogle Scholar
  3. Blouin RA, and Stoeckel K. Cefetamet Pivoxil Clinical Pharmacokinetics. Clin. Pharmacokinet 1993; 25:172–188PubMedCrossRefGoogle Scholar
  4. Bodor N, Sloan KB, Kaminski JJ, Shih C, and Pogany S. A Convenient Synthesis of (Acyloxy)Alkyl ?-Ethers of Phenols. J Org Chem 1983; 48:5280–5284CrossRefGoogle Scholar
  5. Brass EP. Pivalate-Generating Prodrugs and Carnitine Homeostasis in Man. Pharmacol Rev 2002; 54:589–598PubMedCrossRefGoogle Scholar
  6. Brass EP, Mayer MD, Mulford, DJ, Stickler TK, and Hoppel CL. Impact on Carnitine Homeostasis of Short-Term Treatment with the Pivalate Prodrug Cefditoren Pivoxil. Clin Pharmacol Ther 2003; 73:338–347PubMedCrossRefGoogle Scholar
  7. Bretschneider B, Brandsch M, and Neubert R. Intestinal Transport of β-Lactam Antibiotics: Analysis of the Affinity at the H+/Peptide Symporter (PEPT1), the Uptake Into Caco-2 Cell Monolayers and the Transepithelial Flux. Pharm Res 1999; 16: 55–61PubMedCrossRefGoogle Scholar
  8. Bundgaard H. Design of Prodrugs: Bioreversible Derivatives for Various Functional Groups and Chemical Entities. In: Bundgaard, H. Design of Prodrugs. New York, NY Elsevier Science Publishing; 1985:1–92Google Scholar
  9. Dantizg AH, Duckworth DC, and Tabas LB. Transport Mechanisms Responsible of the Absorption of Loracarbef, Cefixime and Cefuroxime Axetil into Human Intestinal Caco-2 Cells. Biochim Biophys Acta 1994, 1191:7–13CrossRefGoogle Scholar
  10. Darkes MJM, and Plosker GL. Cefditoren Pivoxil. Drugs 2002; 62:319–338PubMedCrossRefGoogle Scholar
  11. English AR, Girard D, Jasys VJ, Martingano RJ, and Kellogg MS. Orally Effective Acid Prodrugs of the Beta-Lactamase Inhibitor Sulbactam. J Med Chem 1990; 33:344–347PubMedCrossRefGoogle Scholar
  12. Felmingham D, Robbins MJ, Ghosh G, Bhogal H, Mehta MD, Leakey A, Clark S, Dencer A, Ridgway GL, and Gruneberg RN. An In Vitro Characterization of Cefditoren, a New Oral Cephalosporin. Drug Exp Clin Res 1994; 20(4):127–147Google Scholar
  13. Finn A, Straughn A, Meyer M, and Chubb J. Effect of Dose and Food on the Bioavailability of Cefuroxime Axetil. Biopharm Drug Dispos 1987; 8:519–526.PubMedCrossRefGoogle Scholar
  14. Iwai N, Nakamura H, Miyazu M, and Watanabe Y. Pharmacokinetic, Bacteriological and Clinical Evaluation of Cefditoren Pivoxil in Pediatrics. Jpn J Antibiot 1994; 47: 181–194PubMedGoogle Scholar
  15. Jansen ABA, and Russell TJ. Some Novel Penicillin Derivatives. J Chem Soc Abstracts 1965:2127–2132.Google Scholar
  16. Jones RN, Biedenbach DJ, Croco MA, and Barrett MS. In Vitro Evaluation of a Novel Orally Administered Cephalosporin (Cefditoren) Tested Against 1249 Recent Clinical Isolates of Haemophilus Influenzae, Moraxella Catarrhalis, and Streptococcus Pneumoniae. Diagn Micr Infec Dis. 1998; 31:573–578CrossRefGoogle Scholar
  17. Jones RN, Pfaller M, Jacobs MR, Appelbaum PC, and Fuchs PC. Cefditoren In Vitro Activity and Spectrum: a Review of International Studies Using Reference Methods. Diagn Micr Infec Dis 2001; 41:1–14CrossRefGoogle Scholar
  18. Kees F, and Grobecker H. Systematics of Beta-Lactams: Chemical Properties and Structure Activity Relationship of Oral Cephalosporins. Antibiot Chemother (Basel) 1995; 47 (Oral Cephalosporins):1–7PubMedGoogle Scholar
  19. Li JT, Hou F, Lu H, Li TY, and Li H. Phase 1 Clinical Trial of Cefditoren Pivoxil (ME1207): Pharmacokinetics in Healthy Volunteers. Drug Exp Clin Res 1997; 23:145–150Google Scholar
  20. Mori A, Meguro H, Terashima I, and Fujii R. A Clinical Study on Cefditoren Pivoxil Granules in the Pediatric Field. Jpn J Antibiot 1993; 46:577–588PubMedGoogle Scholar
  21. Nakamura K, Kawahara M, Kasai T, Takasugi M, and Meiji SKK. Pharmacokinetics of Cefditoren Pivoxil Oral Preparations. Kagaku Ryoho no Ryoiki 1995; 11:721–731.Google Scholar
  22. Parsons RL, Hossack GA, and Paddock GM. Pharmacokinetics of Pivmecillinam. Brit J Clin Pharmacother 1997; 4:267–273Google Scholar
  23. Ruiz-Balaguer N, Nacher A, Casabo VG, and Merino-Sanjuan M. Intestinal Transport of Cefuroxime Axetil in Rats: Absorption and Hydrolysis Process. Int J Pharm 2002; 234:101–111PubMedCrossRefGoogle Scholar
  24. Saitoh H, Aungst BJ; Tohyama M, Hatakeyama Yuko, Ohwada K, Kobayashi M, Fujisaki, H, and Miyazaki K. In Vitro Permeation of β-Lactam Antibiotics across Rat Jejunum and its Correlation with Oral Bioavailability in Humans. Brit J Clin Pharmacol 2002; 54:445–448CrossRefGoogle Scholar
  25. Sakagami K, Atsumi K, Tamura A, Yoshida T, Nishihata K, and Fakatsu S. Synthesis and Oral Activity of ME1207, A New Orally Active Cephalosporin. J Antibiot 1990; 43: 1047–1050.PubMedGoogle Scholar
  26. Sakagami K, Atsumi K, Yamamoto Y, Tamura A, Yoshida T, Nishihata K, and Fakatsu S. Synthesis and Oral Activity of Pivaloyloxymethyl 7-[(Z)-2-(2-Aminothiazol-4-yl)-2-Methoxyiminoacetamido]-3(Z)-(4-Methylthiazole-5-yl)Vinyl-3-Cephem-4-Carboxylate (ME1207) and Its Related Compound Chem Pharm Bull. 1991; 39:2433–2436PubMedGoogle Scholar
  27. Shimada K. Significant Role of New Oral Cephem Antibiotics. Focused on Cefditoren Pivoxil: Discussion. Jpn J Antibiot 1994; 47: 951–966.PubMedGoogle Scholar
  28. Silverman RB. The Organic Chemistry of Drug Design and Drug Action. Burlington, MA: Elsevier Academic Press; 2004. 617pGoogle Scholar
  29. Stella, VJ. Prodrugs. Overview and Definition. In Higuchi T, Stella V. ACS Symposium Series 14. American Chemical Society: Washington, DC; 1975; 14(Prodrugs Novel Drug Delivery Systems):1–115Google Scholar
  30. Stella VJ, Martodihardjo SR, and Venkatramana M. Aqueous Solubility and Dissolution Rate Does Not Adequately Predict in Vivo Performance: A Probe Utilizing Some N-Acyloxymethyl Phenytoin Prodrugs. J Pharm Sci 1999, 88:775–779.PubMedCrossRefGoogle Scholar
  31. Stoeckel K, Hayton WL, and Edwards DJ. Clinical Pharmacokinetics of Oral Cephalosporins. Antibiot Chemother (Basel) 1995; 47 (Oral Cephalosporins):34–71PubMedGoogle Scholar
  32. Sugita R, Deguchi K, Kimura S, Harada S, Fujimaki Y, Watanabe H, Naito M, Nomura T; Tanaka M, Komatsu N, Shimizu K, Yoshida Y, and Okano K. Efficacy of Cefditoren Pivoxil in the Treatment of Acute Otitis Media Due to Benzylpenicillin-Insensitive Streptococcus Pneumoniae. Jpn J Antibiot 1996; 49:386–98PubMedGoogle Scholar
  33. Tsuji A, Hirooka H, Terasaki T, Tamai I, and Nakashima E. Saturable Uptake of Cefixime, a New Oral Cephalosporin without an ?-Amino Group, by the Rat Intestine. J Pharm Pharmacol 1987; 39:272–277PubMedGoogle Scholar
  34. von Daehne W, Frederiksen E, Gundersen E, Lund E, Mørch P, Petersen HJ, Roholt K, Tybring L, and Godtfredsen WO. Acyloxylmethyl Esters of Ampicillin. J Med Chem 1970; 13:607–612PubMedCrossRefGoogle Scholar
  35. Yoshimura Y, Hamaguchi N, and Yashiki T. Synthesis and Relationship Between Physiochemical Properties and Oral Absorption of Pivaloxymethyl Esters of Parenteral Cephalosporins. Int J Pharm 1985, 23:117–129CrossRefGoogle Scholar
  36. Zmuidinavicius D, Didziapetris R, Japertas P, Avdeef A, and Petrauskas A. Classification Structure-Activity relations (C-SAR) in Prediction of Human Intestinal Absorption. J Pharm Sci 2003; 92: 621–633.PubMedCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2007

Authors and Affiliations

  • Tarra Fuchs
    • 1
  1. 1.Sunesis PharmaceuticalsSouth San FranciscoUSA

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