Keywords : ME1206, renal excretion, tubular secretion, transport system for anions, stop-flow analysis method, <I>p</I>-aminohippuric acid Renal excre
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1 Keywords : ME1206, renal excretion, tubular secretion, transport system for anions, stop-flow analysis method, <I>p</I>-aminohippuric acid Renal excretion mechanism of ME1206, an active form of a novel oral cephalosporin antibiotic ME1207, in rats, rabbits and dogs. Takashi KURIBAYASHI, Jun-ichi OKAMOTO and Izumi KOMIYA Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., 760, Morooka-cho, Kohoku-ku, Yokohama 222, Japan Summary The renal excretion mechanism of ME1206, an active form of a novel oral cephalosporin antibiotic ME1207, was studied in rats using the renal clearance method and in rabbits and dogs applying the stop-flow analysis method. Excretion ratio (ER) was 3.64 in rats when ME1206 was administered alone. In contrast, the ER was when the tubular secretion was inhibited by iodopyracet administered con comitantly. These results indicate that ME1206 is excreted into urine not only by the glome rular filtration but also by the tubular secretion in rats. In dogs, the ME1206 stop-flow pattern showed neither secretion nor reabsorption peak when ME1206 was administered with <I>p</I>-aminohippuric acid(pah) as a marker substance for prox imal tubular function. On the other hand, except for PAH, there was a small peak showing the tubular secretion. These results suggest that ME1206 is mainly excreted in dogs by the glomerular filtration with small contribution of the proximal tubular secretion. PAH inhibite d a weak secretion of ME1206 competing with the transport system for organic anions. In rabbits, there was an obvious secretion peak of ME1206 even in the presence of PAH. This peak disappeared completely by the coadministration of probenecid. Accordingly, ME 1206 is extensively secreted by the proximal tubules in addition to the glomerular filtration in rabbits. In summary, the mechanism of renal excretion of ME1206 differs among animal species. Moreover, it is suggested that the tubular secretion marker in the stop-flow analysis method should be substances which will be secreted by another transport system from that for the test substance.
2 Fig. 1 Chemical structures of ME 1207 (A) and ME1206 (B)
3
4 Table I HPLC conditions of ME1206, iodopyracet and p-aminohippuric acid (PAH)
5 Table 11 Effect of iodopyracet on the excretion ratio (ER) of ME1206 in rats
6 Fig. 2 Stop-flow pattern of ME1206 with p-aminohippuric acid in the dog before administration of probenecid ;... after administration of probenecid, (A) ME1206 ; (B) p-aminohippuric acid ; (C) Na ; (D) K ; (E) Creatinine ; (F) Inulin
7 Fig. 3 Stop-flow pattern of ME1206 without p-aminohippuric acid in the dog before administration of probenecid ;... after administration of probenecid, (A) ME 1206 ; (B) N a ; (C) K ; (D) Creatinine (E) Inulin
8 Fig. 4 Stop-flow pattern of ME1206 with p aminohippuric acid in the rabbit before administration of probenecid;..., after administration of probenecid, (A) ME 1206 ; (B) p-aminohippuric acid ; (C)Na ; (D)K ; (E)Creatinine; (F) Inulin
9 1) Tamura, A., Okamoto, R., Yoshida, T., Yamamoto, H., Kondo, S., Inoue, M. and Mitsuhashi, S. : In vitro and in vivo antibacterial activities of ME1207, a new oral cephalosporin. Antimicrob. Agents Chemother., 32: (1988). 3) Shimada, J., Yamaji, T., Miyahara, T., Ueda, Y., Kawabata, T., Sugeno, K., Yoshida, T. and Nakamura, M.: Renal disposition of moxalactam in experimental animals as revealed by stop-flow analysis. Antimicrob. Agents Chemother., 23 : 8-14 (1983).
10 6) Inui, K., Okano, T., Takano, M., Kitazawa, S. and Hori, R.: Carrier mediated transport of amino-cephalosporins by brush border membrane - vesicles isolated from rat kidney cortex. Biochem. Pharmacol., 32 : (1983). 7) Inui, K., Okano, T., Takano, M., Saito, H. and Hori, R. : Carrier-mediated transport of cephalexin via the dipeptide transport system in rat renal brush-border membrane vesicles. Biochim. Biophys. Acta, 769 : (1984). 8) Dische, Z. and Borenfreund, E.: A new spectrophotometric method for detection and determination of keto sugars and trioses. J. Biol. Chem., 192: (1951). 9) Malvin, R.L., Wilde, W.S. and Sullivan, L.P. : Localization of nephron transport by stop flow analysis. Am. J. Physiol., 194: (1958). 10) Komiya, I.: Urine flow dependence of renal clearance and interrelation of renal reabsorption and physicochemical properties of drugs. Drug Metab. Dispos., 14 : (1986). 11) Gower, P.E. and Dash, C.H. : The pharmacokinetics of cefuroxime after intravenous injection. Europ. J. clip. Pharmacol., 12 : (1977). 12) Matsui, H. and Okuda, T. : Renal tubular mechanisms for excretion of cefpiramide(sm-1652) in association with its long-lasting pharmacokinetic properties. J. Pharmacobio-Dyn., 11 :67-73 (1988). 13) Yamazaki, I., Shirakawa, Y. and Fugono, T. : Comparison of the renal excretory mechanisms of cefmenoxime and other cephalosporins : effect of para-aminohippurate on renal clearance and intrarenal distribution of cephalosporins in rabbits. J. Antibiot., 34 : (1981). -
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