Ehlhardt W J, Sullivan H R, Wood P G, Woodland J M, Hamilton M, Hamilton C, Cornpropst D, Grindey G B, Worzalla J F, Bewley J R
Department of Drug Metabolism, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285.
J Pharm Sci. 1993 Jul;82(7):683-8. doi: 10.1002/jps.2600820703.
The absorption and pharmacokinetics of sulofenur [N-(indan-5-sulfonyl)-N'-(4-chlorophenyl)urea, LY186641] and its major metabolites were examined in mice, rats, monkeys, and dogs. The compound is a diarylsulfonylurea currently being evaluated as an oncolytic agent in phase I and II trials. In all species, sulofenur was well absorbed after an oral dose, but over a prolonged period, and sulofenur exhibited a fairly long half-life of elimination from plasma. These values ranged from 6 h in rats up to 30, 110, and 200 h in mice, monkeys, and dogs, respectively, at doses (240-1000 mg/m2) within the range of those used in clinical trials. Experiments describing the high degree of binding of sulofenur to plasma proteins (consistently > 99%) help to explain these relatively long half-lives. There is, however, a large difference between these plasma half-lives in the species studied. Sulofenur was previously found to be extensively metabolized to products that are excreted primarily into the urine. In this study, its major metabolites, which are found mainly in the urine, were also minor components of the drug-related material (< 10% of the sulofenur concentrations) in the plasma of rats treated with sulofenur. The absorption, binding characteristics, and elimination of these major metabolites after their administration to rats were also compared with sulofenur.(ABSTRACT TRUNCATED AT 250 WORDS)
研究了舒洛苯脲[N-(茚满-5-磺酰基)-N'-(4-氯苯基)脲，LY186641]及其主要代谢产物在小鼠、大鼠、猴和犬体内的吸收及药代动力学情况。该化合物为二芳基磺酰脲类，目前正处于Ⅰ期和Ⅱ期试验，作为溶瘤剂进行评估。在所有物种中，口服舒洛苯脲后吸收良好，但持续时间较长，且舒洛苯脲从血浆中消除的半衰期相当长。在临床试验所用剂量（240 - 1000 mg/m²）范围内，这些半衰期值分别为：大鼠6小时，小鼠30小时，猴110小时，犬200小时。描述舒洛苯脲与血浆蛋白高度结合（始终>99%）的实验有助于解释这些相对较长的半衰期。然而，在所研究的物种中，这些血浆半衰期存在很大差异。之前发现舒洛苯脲可广泛代谢为主要经尿液排泄的产物。在本研究中，其主要代谢产物主要存在于尿液中，在用舒洛苯脲处理的大鼠血浆中，也是药物相关物质的次要成分（<舒洛苯脲浓度的10%）。还将这些主要代谢产物给予大鼠后其吸收、结合特性及消除情况与舒洛苯脲进行了比较。（摘要截短至250字）
