Dixon C M, Saynor D A, Andrew P D, Oxford J, Bradbury A, Tarbit M H
Department of Drug Metabolism III, Glaxo Group Research Ltd., Ware, Herts, UK.
Drug Metab Dispos. 1993 Sep-Oct;21(5):761-9.
Sumatriptan is a new 5HT1-like agonist that has proved a novel and effective treatment for migraine. The disposition of the 14C-radiolabeled drug in laboratory animals and humans after oral and parenteral administration is described. Oral absorption of sumatriptan is essentially complete in dogs and rabbits, but only approximately 50% in rat. In humans, at least 57% of an oral dose is absorbed. Bioavailabilities are species dependent (14, 23, 37, and 58% in humans, rabbits, rats, and dogs) reflecting differing degrees of first-pass metabolism. These data correlate well with hepatic extraction ratios, which are highest in rabbits and humans and lowest in dogs. Renal clearance is significant in all species and exceeds the glomerular filtration rate in rats, rabbits, and humans, but not in dogs. The compound is a weak base that shows widespread tissue distribution, including passage across the placental barrier and into milk, but low CNS penetration. Protein binding of sumatriptan is low in all species. Elimination half-lives of sumatriptan are approximately 1 hr in rats and rabbits, and approximately 2 hr in dogs and humans. In all species the majority of the absorbed dose is renally excreted, predominantly as the indole acetic acid metabolite and unchanged drug. Interesting species differences are evident in the metabolism of sumatriptan. Thus, in humans, the indole acetic acid metabolite is excreted partly as a glucuronide, whereas in animals conjugation of this metabolite is not apparent. In addition, demethylation of the sulfonamide side chain of the drug is evident in rodent and lagomorph species only.
舒马曲坦是一种新型的5HT1样激动剂，已被证明是治疗偏头痛的一种新颖且有效的药物。本文描述了14C放射性标记药物在实验动物和人类经口服和肠胃外给药后的处置情况。舒马曲坦在犬和兔体内的口服吸收基本完全，但在大鼠体内仅约50%。在人类中，口服剂量至少57%被吸收。生物利用度因物种而异（在人类、兔、大鼠和犬中分别为14%、23%、37%和58%），反映了首过代谢程度的不同。这些数据与肝脏提取率密切相关，肝脏提取率在兔和人类中最高，在犬中最低。在所有物种中，肾清除率都很显著，在大鼠、兔和人类中超过肾小球滤过率，但在犬中则不然。该化合物是一种弱碱，显示出广泛的组织分布，包括穿过胎盘屏障和进入乳汁，但中枢神经系统渗透率较低。舒马曲坦在所有物种中的蛋白结合率都很低。舒马曲坦在大鼠和兔体内的消除半衰期约为1小时，在犬和人类中约为2小时。在所有物种中，吸收剂量的大部分通过肾脏排泄，主要以吲哚乙酸代谢物和未改变的药物形式排泄。舒马曲坦的代谢存在明显的物种差异。因此，在人类中，吲哚乙酸代谢物部分以葡萄糖醛酸苷的形式排泄，而在动物中这种代谢物的结合并不明显。此外，该药物磺酰胺侧链的去甲基化仅在啮齿动物和兔形目动物中明显。
