二肽基肽酶-4抑制剂的临床药代动力学比较。

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戈莱特利LK，德雷纳CC，麦克德莫特MT

二肽基肽酶-4抑制剂的临床药代动力学比较。

临床药典杂志，2012 Aug 1;51(8):501-14。doi: 10.2165 / 11632930-000000000-00000。

PubMed ID

22686547 (PubMed视图

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摘要

二肽基肽酶-4 (DPP-4)抑制剂共同构成了目前独特的2型糖尿病患者疾病管理形式。本综述的目的是比较现有DPP-4抑制剂(阿格列汀、利纳格列汀、沙格列汀、西格列汀和维格列汀)的临床药代动力学，以根据个体患者变量和共发病率确定潜在的选择偏好。DPP-4抑制剂易于口服吸收。口服后，吸收主要发生在小肠，中位时间至最大(峰值)血浆浓度为1 - 3小时。每种剂量的吸收比例从利格列汀约30%到所有其他剂量的75-87%不等。在DPP-4抑制剂之间，最大(峰值)血浆药物浓度和血浆浓度-时间曲线下面积的数值差异存在一个数量级的差异。然而，在所有可用的DPP-4抑制剂中，以降血糖能力衡量的功能能力仍然具有可比性。DPP-4抑制剂的分布受到亲脂性和蛋白质结合的强烈影响。大多数药物的表观分布体积(V(d))在70 ~ 300 L之间，利纳格列汀的V(d)超过1000 L，表明在组织中分布广泛。在血浆和外周组织中与靶蛋白结合对拓宽利格列汀分布有重要影响。 DPP-4 inhibitor metabolism is widely variable, with reported terminal half-lives ranging from approximately 3 to more than 200 hours. Complex relationships between rates of receptor binding and dissociation appear to strongly influence the durations of action of those DPP-4 inhibitors with comparatively shorter half-lives. Durations of activity often are not reflective of clearance and, with the exception of vildagliptin which may be administered either once daily in the evening or twice daily, these medications are effective when used with a once-daily dosing schedule. Saxagliptin and, to a lesser extent, sitagliptin are largely metabolized by hepatic cytochrome P450 (CYP) 3A4 and 3A5 isoforms. With the exception of the primary hydroxylated metabolite of saxagliptin, which is 2-fold less potent than its parent molecule, metabolic products of hepatic biotransformation are minimally active and none appreciably contribute to either the therapeutic or the toxic effects of DPP-4 inhibitors. No DPP-4 inhibitor has been shown to inhibit or to induce hepatic CYP-mediated drug metabolism. Accordingly, the number of clinically significant drug-drug interactions associated with these agents is minimal, with only saxagliptin necessitating dose adjustment if administered concurrently with medications that strongly inhibit CYP3A4. Linagliptin undergoes enterohepatic cycling with a large majority (85%) of the absorbed dose eliminated in faeces via biliary excretion. Other DPP-4 inhibitors predominantly undergo renal excretion, with 60-85% of each dose eliminated as unchanged parent compound in the urine. Systematic reviews of clinical trials suggest that the overall efficacy of DPP-4 inhibitors in patients with type 2 diabetes generally is similar. Apart from these generalizations, pharmacokinetic distinctions that potentially influence product selection are tentative. When considered in total, data reviewed in this report suggest that the best overall balance between potency and the clinical pharmacokinetic characteristics of distribution, metabolism and elimination may be observed with linagliptin followed closely by vildagliptin, saxagliptin, sitagliptin and alogliptin.

引用本文的药物库数据

药物

Alogliptin

Saxagliptin

药物转运蛋白

药物	转运体	种类	生物	药理作用	行动
Saxagliptin	溶质载体家族22个成员8	蛋白质	人类	未知的	底物	细节
Saxagliptin	溶质载体有机阴离子转运体家族成员4C1	蛋白质	人类	未知的	底物	细节