Herman Gary A, Stevens Cathy, Van Dyck Kristien, Bergman Arthur, Yi Bingming, De Smet Marina, Snyder Karen, Hilliard Deborah, Tanen Michael, Tanaka Wesley, Wang Amy Q, Zeng Wei, Musson Donald, Winchell Gregory, Davies Michael J, Ramael Steven, Gottesdiener Keith M, Wagner John A
Merck & Co., Whitehouse Station, NJ 07065, USA.
Clin Pharmacol Ther. 2005 Dec;78(6):675-88. doi: 10.1016/j.clpt.2005.09.002.
Sitagliptin (MK-0431 [(2R)-4-oxo-4-(3-[trifluoromethyl]-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7[8H]-yl)-1-(2,4,5-trifluorophenyl)butan-2-amine]) is an orally active, potent, and selective inhibitor of dipeptidyl peptidase IV (DPP-IV) currently in phase III development for the treatment of type 2 diabetes.
Two double-blind, randomized, placebo-controlled, alternating-panel studies evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of sitagliptin (1.5-600 mg) in healthy male volunteers.
Sitagliptin was well absorbed (approximately 80% excreted unchanged in the urine) with an apparent terminal half-life ranging from 8 to 14 hours. Renal clearance of sitagliptin averaged 388 mL/min and was largely uninfluenced by the dose administered. The area under the plasma concentration-time curve for sitagliptin increased in an approximately dose-dependent manner and was not meaningfully influenced by food. Single doses of sitagliptin markedly and dose-dependently inhibited plasma DPP-IV activity, with approximately 80% or greater inhibition of DPP-IV activity occurring at 50 mg or greater over a 12-hour period and at 100 mg or greater over a 24-hour period. Compared with placebo, sitagliptin produced an approximately 2-fold increase in postmeal active glucagon-like peptide 1 levels. Sitagliptin was well tolerated and was not associated with hypoglycemia.
This study provides proof of pharmacologic characteristics for sitagliptin in humans. By inhibiting plasma DPP-IV activity, sitagliptin increases the postprandial rise in active glucagon-like peptide 1 concentrations without causing hypoglycemia in normoglycemic healthy male volunteers. Sitagliptin possesses pharmacokinetic and pharmacodynamic characteristics that support a once-daily dosing regimen.
西他列汀（MK-0431 [(2R)-4-氧代-4-(3-[三氟甲基]-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪-7[8H]-基)-1-(2,4,5-三氟苯基)丁-2-胺]）是一种口服活性、强效且选择性的二肽基肽酶IV（DPP-IV）抑制剂，目前正处于治疗2型糖尿病的III期开发阶段。
两项双盲、随机、安慰剂对照、交替分组研究评估了单剂量口服西他列汀（1.5 - 600 mg）在健康男性志愿者中的安全性、耐受性、药代动力学和药效学。
西他列汀吸收良好（约80%以原形经尿液排泄），表观终末半衰期为8至14小时。西他列汀的肾清除率平均为388 mL/分钟，且在很大程度上不受给药剂量的影响。西他列汀的血浆浓度 - 时间曲线下面积以近似剂量依赖性方式增加，且不受食物的显著影响。单剂量西他列汀显著且剂量依赖性地抑制血浆DPP-IV活性，在12小时内50 mg及以上剂量以及在24小时内100 mg及以上剂量时，对DPP-IV活性的抑制率约为80%或更高。与安慰剂相比，西他列汀使餐后活性胰高血糖素样肽1水平增加约2倍。西他列汀耐受性良好，且未发生低血糖。
本研究提供了西他列汀在人体中的药理学特征证据。通过抑制血浆DPP-IV活性，西他列汀可增加餐后活性胰高血糖素样肽1浓度的升高，且在血糖正常的健康男性志愿者中不会引起低血糖。西他列汀具有支持每日一次给药方案的药代动力学和药效学特征。
