β-ラクタム系抗生物質の薬学的研究(第11報)Sodium 7-[D(-)-α-(4-Ethyl-2,3-dioxo-1-piperazinecarboxamido)-α-(4-hydroxyphenyl)acetamido]-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylate(T-1551)の代謝について

抄録

Metabolism of Sodium 7-[D (-)-α-(4-ethyl-2, 3-dioxo-1-piperazinecarboxamido)-α-(4-hydroxyphenyl) acetamido]-3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl]-3-cephem-4-carboxylate (T-1551), a new β-lactam antibiotic, was studied in vivo, in situ and in vitro. Only unchanged T-1551 was detected by bioautography in the urine of human and animals receiving T-1551 intramuscularly. When ³H, ¹⁴C double-labeled T-1551 (³H, ¹⁴C-T-1551) was intramuscularly administered to rats, in urine and bile, small amounts of two metabolites, ³H and ¹⁴C radioactive 7-[D (-)-α-3-[2-(N-ethyl-N-oxaloamino) ethyl] ureido-α-(4-hydroxyphenyl) acetamido]-3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl]-3-cephem-4-carboxylic acid (T-1551 A) and ³H radioactive 5-mercapto-1-methyl-1H-tetrazole (T-1551F), and in feces, ¹⁴C radioactive N-formylmethyl D (-)-α-(4-ethyl-2, 3-dioxo-1-piperazinecar-boxamido)-α-(4-hydroxyphenyl) acetamide (T-1551D), were detected by radio thin layer chromatography. Similarly, when T-1551 was administered to monkeys, small amounts of two metabolites, T-1551A and T-1551F, were detected in urine and bile by means of high pressure liquid chromatography (HPLC). Furthermore, quantitative analysis of each metabolite was carried out by HPLC (for separation) and radioactive measurement (for determination). In situ and in vitro, ³H, ¹⁴C-T-1551 was stable in various tissue homogenates, but seemed to change into ¹⁴C-T-1551D and ³H-T-1551F by β-lactamase produced from intestinal flora. In rats, ¹⁴C-T-1551D was hardly absorbed from the gastro-intestinal tracts. On the other hand, when T-1551 was intramuscularly administered to human, small amounts of urinary T-1551A and T-1551F were detected by HPLC similar to the findings in animal studies. We suggest that the metabolism of T-1551 in human was the same as in the animals examined.