Webber C, Stokes C A, Persiani S, Makovec F, McBurney A, Kapil R P, John B A, Houchen T L, D'Amato M, Chasseaud L F
Department of Drug Metabolism, Huntington Life Sciences, Huntingdon, Cambridgeshire, England.
Eur J Drug Metab Pharmacokinet. 2003 Jul-Sep;28(3):201-12. doi: 10.1007/BF03190486.
Single oral doses of 14C-dexloxiglumide were rapidly and extensively absorbed in rats, and eliminated more slowly by females than by males. The respective half-lives were about 4.9 and 2.1 h. Following single intravenous doses, dexloxiglumide was characterised as a drug having a low clearance (6.01 and about 1.96 ml/min/kg in males and females respectively), a moderate volume of distribution (Vss, 0.98 and about 1.1 L/kg in males and females respectively) and a high systemic availability. It was extensively bound to plasma proteins (97%). Dexloxiglumide is mainly cleared by the liver. Its renal clearance was minor. In only the liver and gastrointestinal tract, were concentrations of 14C generally greater than those in plasma. Peak 14C concentrations generally occurred at 1-2 h in males and at 2-4 h in females. Tissue 14C concentrations then declined by severalfold during 24 h although still present in most tissues at 24 h but only in a few tissues (such as the liver and gastrointestinal tract) at 168 h. Decline of 14C was less rapid in the tissues of females than in those of males. Single intravenous or oral doses were mainly excreted in the faeces (87-92%), mostly during 24 h and more slowly from females than from males. Urines contained less than 11% dose. Mean recoveries during 7 days when 14C was not detectable in the carcass except in one female rat ranged between 93-101%. Biliary excretion of 14C was prominent (84-91% dose during 24 h) in the disposition of 14C which was also subjected to facile enterohepatic circulation (74% dose). Metabolite profiles in plasma and selected tissues differed. In the former, unchanged dexloxiglumide was the major component whereas in the latter, a polar component was dominant. Urine, bile and faeces contained several 14C-components amongst which unchanged dexloxiglumide was the most important (eg. up to 63% dose in bile). LC-MS/MS showed that dexloxiglumide was metabolised mainly by hydroxylation in the N-(3-methoxypropyl)pentyl sidechain and by O-demethylation followed by subsequent oxidation of the resulting alcohol to a carboxylic acid.
大鼠单次口服14C标记的右旋洛昔格列胺后吸收迅速且广泛，雌性大鼠的消除速度比雄性大鼠慢。各自的半衰期分别约为4.9小时和2.1小时。单次静脉给药后，右旋洛昔格列胺的特征为一种清除率低（雄性和雌性分别为6.01和约1.96 ml/min/kg）、分布容积中等（稳态分布容积，雄性和雌性分别为0.98和约1.1 L/kg）且全身利用率高的药物。它与血浆蛋白广泛结合（97%）。右旋洛昔格列胺主要通过肝脏清除。其肾清除率较低。仅在肝脏和胃肠道中，14C的浓度通常高于血浆中的浓度。14C的峰值浓度通常在雄性大鼠中于1 - 2小时出现，在雌性大鼠中于2 - 4小时出现。组织中的14C浓度在24小时内下降数倍，尽管在24小时时大多数组织中仍存在，但在168小时时仅在少数组织（如肝脏和胃肠道）中存在。雌性大鼠组织中14C的下降速度比雄性大鼠慢。单次静脉或口服给药后，主要经粪便排泄（87 - 92%），大多在24小时内排泄，雌性大鼠排泄得比雄性大鼠慢。尿液中含药量低于给药剂量的11%。在7天内，除一只雌性大鼠外，尸体中未检测到14C时，平均回收率在93 - 101%之间。14C的胆汁排泄在14C的处置过程中很突出（24小时内为给药剂量的84 - 91%），14C也易于进行肠肝循环（给药剂量的74%）。血浆和选定组织中的代谢物谱不同。在前者中，未变化的右旋洛昔格列胺是主要成分，而在后者中，一种极性成分占主导。尿液、胆汁和粪便中含有几种14C成分，其中未变化的右旋洛昔格列胺是最重要的（例如，胆汁中高达给药剂量的63%）。液相色谱 - 串联质谱法显示，右旋洛昔格列胺主要通过N - (3 - 甲氧基丙基)戊基侧链的羟基化以及O - 去甲基化，随后将生成的醇氧化为羧酸进行代谢。
