比较临床药物动力学dipeptidyl peptidase-4抑制剂。

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戈莱特利路,德雷纳CC,麦克德莫特

比较临床药物动力学dipeptidyl peptidase-4抑制剂。

51 Pharmacokinet。2012年8月1;(8):501 - 14所示。doi: 10.2165 / 11632930-000000000-00000。

PubMed ID
22686547 (在PubMed
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文摘

Dipeptidyl peptidase-4 (DPP-4)抑制剂目前共同构成一个独特的形式的疾病管理与2型糖尿病人。本文的目的是比较的临床药物动力学可用DPP-4抑制剂(alogliptin、linagliptin saxagliptin, sitagliptin和vildagliptin)的目的是识别潜在的选择偏好根据个别病人变量和并发症。口头DPP-4抑制剂很容易吸收。口服摄入后,主要发生在小肠吸收,中位数乘以最大(峰)血浆浓度从1到3个小时。每个剂量范围从吸收大约30%的分数与linagliptin为所有其他75 - 87%。数值差异最大(峰)血浆药物浓度和区域之间的血浆浓度时间曲线DPP-4抑制剂随一个数量级。然而,功能容量的测量的降糖的能力仍然比较在所有可用DPP-4抑制剂。DPP-4抑制剂分布强烈影响亲油性和蛋白结合。明显的分布(V (d))对大多数代理范围从70年到300年L . Linagliptin展品V (d)超过1000 L,表明广泛分布到组织。绑定到目标蛋白质在等离子体和外围组织施加重大影响扩大linagliptin分布。 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.

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