ABSORPTION, DISTRIBUTION, METABOLISM AND EXCRETION OF SISOMICIN IN MICE, RATS AND DOGS

• Published in: Japanese journal of antibiotics Vol. 32; no. 3; pp. 312 - 324
• Main Authors: IKEDA, CHIEKO, TACHIBANA, AKIO, YANO, KUNIICHIRO
• Format: Journal Article
• Language: Japanese
• Published: Japan Japan Antibiotics Research Association 01.03.1979
• Subjects: Absorption; Animals; Bile - metabolism; Blood Proteins - metabolism; Dogs; Gentamicins - metabolism; In Vitro Techniques; Kidney - metabolism; Male; Mice; Protein Binding; Rats; Sisomicin - blood; Sisomicin - metabolism; Sisomicin - urine; Tissue Distribution
• ISSN: 0368-2781; 2186-5477
• DOI: 10.11553/antibiotics1968b.32.312

The biological assay method of sisomicin was examined, and then absorption, distribution, metabolism and excretion of sisomicin after a single parenteral administration of 10mg/kg to mice, rats and dogs, and the persistence in the kidney and binding to serum protein were compared with those of gentamicin. Agar-well and, cup methods using. Bacillus Subtilis as the test organism and nutrient agar as the medium revealed higher sensitivity than paper-disc method and gave the suitable standard curves. Paper-disc method, however, seems to be applicable to the assay for the usual concentration of sisomicin in the body fluids after treatment. The standard curve of sisomicin was markedly influenced by pH of medium and diluent, the higher the pH of them and the larger of the inhibited zone size. Human plasma and Moni-trol I as the diluent of standard solution gave larger zone size than phosphate buffer solution at pH 8.0, but no difference between the two diluents of human plasma and Moni-trol I was observed. Sisomicin was extremely well-absorbed from injected sites of all animals such as mice, rats and dogs. Plasma levels of sisomicin following subcutaneous and intramuscular injections into animals decreased rapidly and exponentially. The biological half-life times of plasma concentration curves of sisomicin had a tendency to become longer in bigger animal species as 19.4, 23.5 and 75.6 minutes for mice, rats and dogs, respectively. Sisomicin was rapidly distributed into various organs of mice and rats after subcutaneous and intramuscular iNections. The concentration in kidney was very high and persisted longer than in plasma and other tissues. The concentrations in lung, heart, spleen and testis, were lower than those of plasma and decreased rapidly. Especially, the concentrations in liver of both animals were the lowest among the all tissues tested. Total excretion rates in urine during 48 hours after administration were 68.9%, 81.2% and 92.7% of dose in mice, rats and dogs, respectively, whereas the excretion in bile during 24 hours was about 0.1% of dose in rats. The large part of sisomicin parenterally administered in animals was recovered in urine within 6 hours. However, very small amount was consistently excreted in urine for the period of 24-48 hours after injection. No active metabolite was found in urine of rats and dogs treated with sisomicin by means of thin-layer chromatography and bioautography. Persistence of sisomicin in the organs of rats and dogs for 14 weeks and 7 weeks, respectively, after a single intramuscular injection was investigated. The tissue concentration-time curve for the whole kidney of rats was divided in the two characteristics of half-life times which were 2.4 weeks during the first 6 weeks and 8.6 weeks between the sixth and fourteenth week after treatment. In dogs, the concentration of sisomicin, in renal cortex decreassed more rapid with a half-life time of 1, 4 weeks than those in rats. On the other hand, the concentration in renal medulla and urine was extremely lower than in renal cortex and only detected until the first to third week after injection. By means of ultrafiltration method, only small amounts, about 10%, of bound sisomicin to human, dog and rat serum were observed, but the percentages of bound sisomicin were 22.4% and 26.6% in rabbit serum and in 4% solution of human serum albumin, respectively. No significant difference was observed in the pharmacological results between sisomicin and gentamicin, except for the biological assay method of sisomicin.