Ong Voon, Flanagan Shawn, Fang Edward, Dreskin Howard J, Locke Jeffrey B, Bartizal Kenneth, Prokocimer Philippe
Cubist, San Diego, California
Cubist, San Diego, California.
Drug Metab Dispos. 2014 Aug;42(8):1275-84. doi: 10.1124/dmd.113.056697. Epub 2014 May 29.
Tedizolid phosphate is a novel antibacterial prodrug with potent activity against Gram-positive pathogens. In vitro and in vivo studies demonstrated that the prodrug is rapidly converted by nonspecific phosphatases to the biologically active moiety tedizolid. Single oral dose radiolabeled (14)C-tedizolid phosphate kinetic studies in human subjects (100 µCi in 204 mg tedizolid phosphate free acid) confirmed a rapid time to maximum tedizolid concentration (Tmax, 1.28 hours), a long terminal half-life (10.6 hours), and a Cmax of 1.99 µg/ml. Metabolite analysis of plasma, fecal, and urine samples from rats, dogs, and humans confirmed that tedizolid is the only measurable metabolite in plasma after intravenous (in animals only) or oral administration and that tedizolid sulfate is the major metabolite excreted from the body. Excellent mass balance recovery was achieved and demonstrated that fecal excretion is the predominant (80-90%) route of elimination across species, primarily as tedizolid sulfate. Urine excretion accounted for the balance of drug elimination but contained a broader range of minor metabolites. Glucuronidation products were not detected. Similar results were observed in rats and dogs after both intravenous and oral administration. The tedizolid metabolites showed less potent antibacterial activity than tedizolid. The observations from these studies support once daily dosing of tedizolid phosphate and highlight important metabolism and excretion features that differentiate tedizolid phosphate from linezolid.
磷酸泰地唑胺是一种新型抗菌前体药物，对革兰氏阳性病原体具有强效活性。体外和体内研究表明，该前体药物可被非特异性磷酸酶迅速转化为具有生物活性的部分——泰地唑胺。在人体受试者中进行的单次口服放射性标记（14C）磷酸泰地唑胺动力学研究（204毫克磷酸泰地唑胺游离酸中含100微居里）证实，达到泰地唑胺最大浓度的时间很快（Tmax为1.28小时），终末半衰期较长（10.6小时），Cmax为1.99微克/毫升。对大鼠、犬和人类的血浆、粪便及尿液样本进行的代谢物分析证实，静脉注射（仅在动物中）或口服给药后，血浆中唯一可检测到的代谢物是泰地唑胺，硫酸泰地唑胺是从体内排出的主要代谢物。实现了出色的质量平衡回收率，表明粪便排泄是各物种消除药物的主要途径（80 - 90%），主要以硫酸泰地唑胺的形式排出。尿液排泄占药物消除的其余部分，但含有更广泛的次要代谢物。未检测到葡萄糖醛酸化产物。在大鼠和犬静脉注射及口服给药后均观察到类似结果。泰地唑胺的代谢物显示出比泰地唑胺弱的抗菌活性。这些研究的观察结果支持磷酸泰地唑胺每日一次给药，并突出了将磷酸泰地唑胺与利奈唑胺区分开来的重要代谢和排泄特征。
