Fouda H G, Avery M J, Dalvie D, Falkner F C, Melvin L S, Ronfeld R A
Drug Metabolism Department, Pfizer, Inc., Groton, CT 06340, USA.
Drug Metab Dispos. 1997 Feb;25(2):140-8.
Tenidap is a new antirheumatic drug currently undergoing clinical evaluation. It inhibits production and activity of cytokines in vivo and causes significant reductions in plasma markers of disease activity in rheumatoid arthritis. After the oral administration of C-14 labeled tenidap, bile, urine and plasma were examined by HPLC and atmospheric pressure tandem mass spectrometry. Label is excreted primarily in bile/feces and the remainder in urine, with good recoveries. Numerous metabolites were identified and the structures of most were confirmed by comparison with authentic synthetic samples. Hydroxylation in several positions on both the oxindole and thienyl rings of tenidap represents the major routes of metabolism; most of these metabolites are subsequently conjugated. The glucuronide of 5'-hydroxytenidap, excreted primarily in bile, is the major metabolite, constituting about one third of the oral dose recovered. Other pathways include dihydroxylation and methoxylation on the thienyl ring. An unusual reduction of hydroxytenidap took place, resulting in the formation of a novel thiolactone analog. Anaerobic incubation with rat cecal contents generated the thiolactone metabolite, suggesting the involvement of gut microflora.
替硝唑是一种正在进行临床评估的新型抗风湿药物。它在体内抑制细胞因子的产生和活性，并能显著降低类风湿性关节炎患者疾病活动的血浆标志物水平。口服C-14标记的替硝唑后，通过高效液相色谱法和大气压串联质谱法对胆汁、尿液和血浆进行检测。标记物主要通过胆汁/粪便排出，其余通过尿液排出，回收率良好。鉴定出了多种代谢物，大多数代谢物的结构通过与真实合成样品比较得以确认。替硝唑的异吲哚环和噻吩环上多个位置的羟基化是主要代谢途径；这些代谢物大多随后会发生结合反应。5'-羟基替硝唑的葡萄糖醛酸苷主要通过胆汁排出，是主要代谢物，约占口服剂量回收量的三分之一。其他途径包括噻吩环上的二羟基化和甲氧基化。发生了羟基替硝唑的异常还原反应，形成了一种新型硫代内酯类似物。与大鼠盲肠内容物进行厌氧孵育产生了硫代内酯代谢物，提示肠道微生物群参与其中。
