Mizojiri K, Futaguchi S, Norikura R, Katsuyama Y, Nagasaki T, Yoshimori T, Nakanishi M
Developmental Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Antimicrob Agents Chemother. 1995 Jul;39(7):1445-53. doi: 10.1128/AAC.39.7.1445.
[pivaloyl-14C]S-1108, which is 14C labeled at the pivalic acid moiety of the pivaloyloxymethyl side chain of S-1108, was administered orally to rats and dogs, and the disposition of pivalic acid cleft from S-1108 was examined. Besides pivaloylcarnitine and pivaloylglucuronide, pivaloylglycine was identified in dog urine as a metabolite of pivalic acid by thin-layer chromatography and high-performance liquid chromatography analysis. The concentrations in the plasma of rats to which doses of 6.65, 26.6, and 532 mg/kg of body weight were administered showed dose-proportionate levels. The radioactivity was eliminated rapidly, with a half-life of approximately 3 h until 24 h at both the 6.65- and 26.6-mg/kg doses. Free pivalic acid in plasma accounted for more than 80% of the concentration of radioactivity. Radioactivity was distributed throughout the body and was eliminated quickly at a rate similar to that of radioactivity from plasma. Most of the absorbed radioactivity was excreted in the urine, and it was completed within 24 h after administration. In dogs, the half-life of radioactivity in plasma was longer than that in the rats. The ratio of free pivalic acid in plasma was 60 to 70% of the radioactivity in plasma. The concentration of radioactivity in the liver, cortex of the kidney, and skeletal muscle 144 h after oral dosing was more than 10 times higher than the concentration in plasma for all doses. Urinary excretion in dogs was slower than that in rats. The differences in the disposition of pivalic acid between dogs and rats may account for differences in the degree of skeletal muscle disorders. The safety in humans of S-1108 given at 200 mg three times a day is discussed in relation to the metabolic formation of the carnitine conjugate of pivalic acid and the reduction of the carnitine concentration in plasma.
[新戊酰基 - ¹⁴C]S - 1108在S - 1108新戊酰氧基甲基侧链的新戊酸部分标记有¹⁴C，将其口服给予大鼠和狗，并研究了从S - 1108裂解出的新戊酸的处置情况。除了新戊酰肉碱和新戊酰葡萄糖醛酸外，通过薄层色谱法和高效液相色谱分析在狗尿中鉴定出新戊酰甘氨酸是新戊酸的一种代谢产物。给予体重剂量为6.65、26.6和532 mg/kg的大鼠血浆中的浓度呈现出剂量成比例的水平。放射性迅速消除，在6.65 - 和26.6 - mg/kg剂量下，直到24小时的半衰期约为3小时。血浆中的游离新戊酸占放射性浓度的80%以上。放射性分布于全身，并以与血浆中放射性相似的速率迅速消除。大部分吸收的放射性在尿液中排泄，给药后24小时内完成。在狗中，血浆中放射性的半衰期比大鼠长。血浆中游离新戊酸的比例为血浆中放射性的60%至70%。口服给药144小时后，肝脏、肾皮质和骨骼肌中的放射性浓度比所有剂量下血浆中的浓度高10倍以上。狗的尿排泄比大鼠慢。狗和大鼠之间新戊酸处置的差异可能解释了骨骼肌疾病程度的差异。关于新戊酸肉碱共轭物的代谢形成以及血浆中肉碱浓度的降低，讨论了每天三次给予200 mg的S - 1108在人体中的安全性。
