Absorption, Metabolism, and Excretion of [14C]Vildagliptin, a Novel Dipeptidyl Peptidase 4 Inhibitor, in Humans
Absorption, Metabolism, and Excretion of [14C]Vildagliptin, a Novel Dipeptidyl Peptidase 4 Inhibitor, in Humans
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DOI：
10.1124/dmd.108.023010
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发表时间：
2009-03-01
影响因子：
3.9
通讯作者：
Howard, Dan
中科院分区：
文献类型：
--
作者：
He, Handan;Tran, Phi;Howard, Dan
（1-[[3-羟基-1金刚烷基）氨基]乙酰基]-2-氰基-(S)-吡咯列丁（维格列汀）是一种口服活性和高选择性的二肽基肽酶4抑制剂，用于治疗2型糖尿病，在4名健康男性受试者中，单次服用[(14)C]维格列汀后，对其吸收、代谢和排泄进行了评估。给药后168 h连续采集血液和全尿、全粪。维格列汀被迅速吸收，在给药后1.1 h达到血药浓度峰值。经计算药物的吸收率至少为85.4%。血浆中主要循环成分为原药和羧酸代谢物（M20.7），分别占血浆总放射性曲线下面积的25.7%（维格列汀）和55% （M20.7）。维格列汀的终末半衰期为2.8 h， 7天内剂量完全回收，其中85.4%从尿中回收（22.6%从原药中回收），其余从粪便中回收（4.54%从原药中回收）。维格列汀在排泄前至少通过四种途径广泛代谢，主要代谢物M20.7是由氰基水解引起的，而不是由细胞色素P450 （P450）酶介导。少量代谢物产生于酰胺键水解（M15.3），葡萄糖醛酸化（M20.2），或氧化维格列汀的吡啶部分（M20.9和M21.6）。不同的代谢途径加上缺乏显著的P450代谢（剂量的1.6%），使得维格列汀对P450抑制剂/诱导药物的潜在药代动力学相互作用不太敏感。此外，由于维格列汀不是P450抑制剂，因此维格列汀不太可能影响P450酶代谢药物的代谢清除率。
The absorption, metabolism, and excretion of (1-[[3-hydroxy-1adamantyl)amino] acetyl]-2-cyano-(S)-pyrrolidine (vildagliptin), an orally active and highly selective dipeptidyl peptidase 4 inhibitor developed for the treatment of type 2 diabetes, were evaluated in four healthy male subjects after a single p. o. 100-mg dose of [(14)C] vildagliptin. Serial blood and complete urine and feces were collected for 168 h postdose. Vildagliptin was rapidly absorbed, and peak plasma concentrations were attained at 1.1 h postdose. The fraction of drug absorbed was calculated to be at least 85.4%. Unchanged drug and a carboxylic acid metabolite (M20.7) were the major circulating components in plasma, accounting for 25.7% (vildagliptin) and 55% (M20.7) of total plasma radioactivity area under the curve. The terminal half-life of vildagliptin was 2.8 h. Complete recovery of the dose was achieved within 7 days, with 85.4% recovered in urine (22.6% unchanged drug) and the remainder in feces (4.54% unchanged drug). Vildagliptin was extensively metabolized via at least four pathways before excretion, with the major metabolite M20.7 resulting from cyano group hydrolysis, which is not mediated by cytochrome P450 (P450) enzymes. Minor metabolites resulted from amide bond hydrolysis (M15.3), glucuronidation (M20.2), or oxidation on the pyrrolidine moiety of vildagliptin (M20.9 and M21.6). The diverse metabolic pathways combined with a lack of significant P450 metabolism (1.6% of the dose) make vildagliptin less susceptible to potential pharmacokinetic interactions with comedications of P450 inhibitors/inducers. Furthermore, as vildagliptin is not a P450 inhibitor, it is unlikely that vildagliptin would affect the metabolic clearance of comedications metabolized by P450 enzymes.