Chakraborty B S, Hawes E M, McKay G, Hubbard J W, Korchinski E D, Midha K K, Choc M G, Robinson W T
College of Pharmacy, University of Saskatchewan, Saskatoon, Canada.
Drug Metabol Drug Interact. 1988;6(3-4):425-37. doi: 10.1515/dmdi.1988.6.3-4.425.
Thioridazine has two major active metabolites, which are formed from S-oxidation of its 2-methylthio group; the sulphoxide, mesoridazine, and the sulphone, sulforidazine. Dose proportionality of the three compounds was investigated for the first time in 11 males after administration of three single oral doses (25, 50, and 100 mg) of thioridazine hydrochloride separated in each case by two weeks. Based on the plasma concentrations of the three analytes over 72 h following each dose, large intersubject variabilities in such parameters as AUCot and Cmax were observed for each of the three compounds. The relationships between dose and parameters such as AUCot and Cmax for each analyte were described by an equation for a straight line (r2 greater than or equal to 0.8). However, the mean apparent distribution and elimination rate constants for thioridazine and mesoridazine and the mean apparent oral clearance for thioridazine decreased significantly with increasing dose, suggesting non-linearity in the elimination of thioridazine at high dose.
硫利达嗪有两种主要活性代谢产物，由其2-甲硫基的S-氧化形成；亚砜（美索达嗪）和砜（磺硫达嗪）。11名男性在分别间隔两周口服三次单剂量（25、50和100毫克）盐酸硫利达嗪后，首次对这三种化合物的剂量比例进行了研究。根据每次给药后72小时内三种分析物的血浆浓度，观察到这三种化合物在AUCot和Cmax等参数上存在较大的个体间差异。每种分析物的剂量与AUCot和Cmax等参数之间的关系用直线方程描述（r2大于或等于0.8）。然而，硫利达嗪和美索达嗪的平均表观分布和消除速率常数以及硫利达嗪的平均表观口服清除率随剂量增加而显著降低，表明高剂量时硫利达嗪的消除存在非线性。
