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Possible Factors Involved in Oral Inactivity of Meropenem, a Carbapenem Antibiotic

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DOI: 10.4236/pp.2012.32027    5,307 Downloads   10,337 Views   Citations

ABSTRACT

Meropenem, a carbapenem antibiotic, is inactive after oral administration and administered exclusively by injection. In this study, in order to address the factors involved in the oral inactivity of meropenem, in vitro permeation characteristics across rat ileal segments was investigated using diffusion cells. Moreover, stability of meropenem was evaluated in the Japanese Pharmacopoeia (JP) 1st and 2nd fluid for disintegration test. Cefotaxime, ceftibuten, and faropenem were used for comparison. The permeation of meropenem across rat ileal segments was approximately 5-fold greater in secretory direction than in absorptive direction. The secretory-oriented transport of meropenem markedly diminished by replacement of D-glucose in the experimental medium with unmetabolizing 3-O-methyl-D-glucose, suggesting that the secretory transport of meropenem was an energy-dependent process. Cefotaxime exhibited extensively secretory-oriented permeation. On the other hand, much weaker directionalities were observed in ceftibuten and faropenem. While meropenem as well as other three β-lactam antibiotics was stable in JP 2nd fluid (pH 6.8), it declined rapidly in JP 1st fluid (pH 1.2). These results suggest that, in addition to the hydrophilic property of meropenem, its instability at gastric pH and secretory transport in the small intestine are possible factors involved in the inactivity of meropenem after oral administration.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

T. Saito, R. Sawazaki, K. Ujiie, M. Oda and H. Saitoh, "Possible Factors Involved in Oral Inactivity of Meropenem, a Carbapenem Antibiotic," Pharmacology & Pharmacy, Vol. 3 No. 2, 2012, pp. 201-206. doi: 10.4236/pp.2012.32027.

References

[1] A. Dalhoff, N. Janjic and R. Echols, “Redefining Penems,” Biochemical Pharmacology, Vol. 71, No. 7, 2006, pp. 1085-1095. doi:10.1016/j.bcp.2005.12.003
[2] G. G. Zhanel, R. Wiebe, L. Dilay, K. Thomson, E. Rubinstein, D. J. Hoban, A. M. Noreddin and J. A. Karlowsky, “Comparative REVIEW of the CARBAPENEMs,” Drugs, Vol. 67, No. 7, 2007, pp. 1027-1052. doi:10.2165/00003495-200767070-00006
[3] M. I. El-Gamal and C. H. Oh, “Current Status of Carbapenem Antibiotics,” Current Opinion of Medicinal Chemistry, Vol. 10, No. 18, 2010, pp. 1882-1887.
[4] G. Bonfiglio, G. Russo and G. Nicoletti, “Recent Developments in Car-bapenems,” Expert Opinion on Investigational Drugs, Vol. 11, No. 4, 2002, pp. 529-544. doi:10.1517/13543784.11.4.529
[5] T. Isoda, H. Ushi-rogochi, K. Satoh, T. Takasaki, I. Yamamura, C. Sato, A. Mihira, T. Abe, S. Tamai, S. Yamamoto, T. Kumagai and Y. Nagao, “Syntheses and Pharmacokinetic Studies of Prodrug Esters for the Development of Oral Carbapenem, L-084,” Journal of Antibiotics (Tokyo), Vol. 59, No. 4, 2006, pp. 241-247. doi:10.1038/ja.2006.34
[6] N. Sato, K. Kijima, T. Koresawa, N. Mitomi, J. Morita, H. Suzuki, H. Hayashi, S. Shibasaki, T. Kurosawa and K. Totsuka, “Population Pharmacokinetics of Tebipenem Pivoxil (ME1211), a Novel Oral Carbapenem Antibiotic, in Pediatric Patients with Otolaryngological Infection or Pneumonia,” Drug Metabolism and Pharmacokinetics, Vol. 23, No. 5, 2008, pp. 434-446. doi:10.2133/dmpk.23.434
[7] E. M. Leslie, R. G. Deeley and S. P. Cole, “Multidrug Resistance Proteins: Role of P-Glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in Tissue Defense,” Toxicology and Applied Pharmacology, Vol. 204, No. 3, 2005, pp. 216-237. doi:10.1016/j.taap.2004.10.012
[8] H. Saitoh, C. Gerard and B. J. Aungst, “The Secretory Intestinal Transport of Some Beta-Lactam Antibiotics and Anionic Compounds: A Mechanism Contributing to Poor Oral Absorption,” Journal of Pharmacology and Experimental Therapeutics, Vol. 278, No. 1, 1996, pp. 205-211.
[9] H. Saitoh, H. Fujisaki, B. J. Aungst and K. Miyazaki, “Restricted Intestinal Absorption of Some Beta-Lactam Antibiotics by an Energy-Dependent Efflux System in Rat Intestine,” Pharmaceutical Research, Vol. 14, No. 5, 1997, pp. 645-649. doi:10.1023/A:1012113430539
[10] P. C. van Krimpen, W. P. van Bennekom and A. Bult, “Penicillins and Cephalosporins. Physicochemical Properties and Analysis in Pharmaceutical and Biological Matrices,” Pharmaceutisch Weekblad, Scientific Edition, Vol. 9, No. 1, 1987, pp. 1-23.
[11] J. W. Mouton and J. N. van den Anker, “Meropenem Clinical Pharmacokinetics,” Clinical Pharmacokinetics, Vol. 28, No. 4, 1995, pp. 275-286. doi:10.2165/00003088-199528040-00002
[12] M. Hikida, K. Kawashima, M. Yoshida and S. Mitsuhashi, “Inactivation of New Carbapenem Antibiotics by Dehydropeptidase-I, from Porcine and Human Renal Cortex,” Journal of Antimicrobial Chemotherapy, Vol. 30, No. 2, 1992, pp. 129-134. doi:10.1093/jac/30.2.129
[13] L. Poirel, J. D. Pitout and P. Nordmann, “Carbapenemases: Molecular Diversity and Clinical Consequences,” Future Microbiology, Vol. 2, No. 5, 2007, pp. 501-512. doi:10.2217/17460913.2.5.501
[14] P. Linden, “Safety Profile of Meropenem: An Updated Review of over 6000 Patients Treated with Meropenem,” Drug Safety, Vol. 30, No. 8, 2007, pp. 657-668. doi:10.2165/00002018-200730080-00002

  
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