Kuo B S, Poole J C, Hwang K K, Cheng H
Drug Metabolism Section, Marion Merrell Dow Inc., Kansas City, MO 64134.
J Pharm Sci. 1993 Jul;82(7):694-8. doi: 10.1002/jps.2600820705.
The pharmacokinetics of a new 5-hydroxytryptamine (5HT3) receptor antagonist, 4-amino-5-chloro-2-[(methylsulfinyl)ethoxy]-N-[2-(diethylamino)ethyl] benzamide (ML-1035, 1), and its sulfone and sulfide metabolites were examined in 12 rats. Each of these compounds (25.4 mumol/kg) was administered to rats intravenously. Their plasma concentrations were measured by high-performance liquid chromatography. These plasma data revealed that 1, a sulfoxide, underwent interconversion with its sulfide metabolite. However, no interconversion was observed between 1 and its sulfone metabolite. Examination of mean times and additional properties of the 1/sulfide metabolite system revealed that total exposure times of 1 and the sulfide metabolite were moderately and weakly, respectively, influenced by the metabolic interconversion process. However, the tissue distribution process strongly influenced the total exposure times of both compounds. The disposition of the sulfone metabolite of 1 was also strongly influenced by the tissue distribution process. In addition, < 3% of the intravenous dose of 1 or the sulfide was available to the general circulation as the sulfone metabolite.
在12只大鼠中研究了一种新型5-羟色胺（5HT3）受体拮抗剂4-氨基-5-氯-2-[(甲基亚磺酰基)乙氧基]-N-[2-(二乙氨基)乙基]苯甲酰胺（ML-1035，1）及其砜和硫化物代谢物的药代动力学。将这些化合物中的每一种（25.4 μmol/kg）静脉注射给大鼠。通过高效液相色谱法测量它们的血浆浓度。这些血浆数据表明，亚砜1与其硫化物代谢物之间发生了相互转化。然而，在1与其砜代谢物之间未观察到相互转化。对1/硫化物代谢物系统的平均时间和其他特性的研究表明，1和硫化物代谢物的总暴露时间分别受到代谢相互转化过程的中度和轻度影响。然而，组织分布过程强烈影响这两种化合物的总暴露时间。1的砜代谢物的处置也受到组织分布过程的强烈影响。此外，静脉注射剂量的1或硫化物中<3%作为砜代谢物进入体循环。
