利格列汀的临床药代动力学和药效学。
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葛瑞菲-莫迪，李志刚，李志刚
利格列汀的临床药代动力学和药效学。
临床药典杂志，2012 july 1;51(7):411-27。doi: 10.2165 / 11630900-000000000-00000。
- PubMed ID
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22568694 (PubMed视图］
- 摘要
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利格列汀是一种口服活性二肽基肽酶(DPP)-4小分子抑制剂，于2011年首次在美国、欧洲、日本和其他地区获得许可，用于改善成人2型糖尿病的血糖控制。利格列汀是第一个也是迄今为止唯一的DPP-4抑制剂和口服降糖药，被批准为单剂量每日一次(5mg)。与其他可用的DPP-4抑制剂相比，利格列汀具有独特的药代动力学/药动力学特征，其特点是靶向介导的非线性药代动力学，浓度依赖的蛋白质结合，最小的肾脏清除率，不需要任何内在或外在因素的剂量调整。单次或多次口服1- 10mg后，利格列汀的最大血药浓度(C(max))和血药浓度-时间曲线(AUC)下面积的增加低于剂量比例。利格列汀口服后迅速吸收，约90分钟后出现C(max)， 4天内达到稳态浓度。在治疗剂量下，稳态C(max) (11-12 nmol/L)和AUC(约150 nmol。h/L)约为单次给药后的1.3倍，表明重复给药后药物积累很少。利格列汀在体外人血浆中表现出浓度依赖性蛋白结合(1 nmol/L时为99%，>30 nmol/L时为75-89%)，表观分布体积大，在组织中分布广泛。利格列汀的非线性药代动力学最好用双室室模型来描述，该模型结合了由高亲和力、可饱和结合到DPP-4引起的靶点介导的药物处置。用该模型估计利格列汀的口服生物利用度约为30%。 Linagliptin has a long terminal half-life (>100 hours); however, its accumulation half-life is much shorter (approximately 10 hours), accounting for the rapid attainment of steady state. The majority of linagliptin is eliminated as parent compound, demonstrating that metabolism plays a minor role in the overall pharmacokinetics in humans. The main, pharmacologically inactive S-3-hydroxypiperidinyl metabolite accounted for approximately 17% of the total drug-related compounds in plasma. Linagliptin is eliminated primarily in faeces, with only around 5% of the oral therapeutic dose excreted in the urine at steady state. Linagliptin potently inhibits DPP-4 (inhibition constant 1 nmol/L), and trough drug concentrations achieved with therapeutic dosing inhibit >80% of plasma DPP-4 activity, the threshold associated with maximal antihyperglycaemic effects in animal models. There are no clinically relevant alterations in linagliptin pharmacokinetics resulting from renal impairment, hepatic impairment, coadministration with food, race, body weight, sex or age. In vitro, linagliptin is a weak substrate and weak inhibitor of cytochrome P450 (CYP) 3A4 and permeability glycoprotein (P-gp) but not of other CYP isozymes or ATP-binding cassette transporters. Clinical studies have revealed no relevant drug interactions when coadministered with other drugs commonly prescribed to patients with type 2 diabetes, including the narrow therapeutic index drugs warfarin and digoxin. Linagliptin plasma exposure is reduced by potent inducers of CYP3A4 or P-gp. Linagliptin has demonstrated a large safety window (>100-fold the recommended daily dose) and clinically relevant antihyperglycaemic effects in patients with type 2 diabetes.
引用本文的药物库数据
- 药物
- 药物转运蛋白
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药物 转运体 种类 生物 药理作用 行动 Linagliptin 22 - 1 蛋白质 人类 未知的底物细节 Linagliptin 溶质载体家族22个成员 蛋白质 人类 未知的抑制剂细节 Linagliptin 溶质载体家族22个成员2 蛋白质 人类 未知的底物抑制剂细节 Linagliptin 溶质载体家族22个成员3 蛋白质 人类 未知的抑制剂细节 - 药物的相互作用Learn More" title="" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
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药物 交互 整合药物之间
软件中的交互Linagliptin 曲唑酮 利格列汀与曲唑酮合用可降低血药浓度。 Linagliptin 米非司酮 利格列汀与米非司酮合用可降低血清浓度。 Linagliptin 利福平 利福平与利格列汀合用可降低利格列汀的血药浓度。 Linagliptin 圣约翰草 利格列汀与圣约翰草合用可降低血清浓度。 Linagliptin Lumacaftor 联合Lumacaftor可降低利格列汀的血药浓度。 Linagliptin 强的松磷酸 利格列汀与磷酸泼尼松龙合用可降低血药浓度。 Linagliptin Tipranavir 利格列汀与替那韦合用可降低血清浓度。 Linagliptin 醋酸地塞米松 利格列汀与醋酸地塞米松合用可降低血清浓度。 Linagliptin Lorlatinib 利格列汀与洛拉替尼合用可降低血清浓度。
