Non-linear increase in GLP-1 levels in response to DPP-IV inhibition in healthy adult subjects
Non-linear increase in GLP-1 levels in response to DPP-IV inhibition in healthy adult subjects
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DOI：
10.1111/j.1463-1326.2007.00742.x
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发表时间：
2008-06-01
影响因子：
5.8
通讯作者：
Hirshberg, Boaz
中科院分区：
文献类型：
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作者：
Dai, Haiqinq;Gustavson, Stephanie M.;Hirshberg, Boaz
目的：二肽基肽酶-IV（DPP-IV）抑制剂是治疗2型糖尿病的一种新的有前途的治疗干预。本研究的目的是探讨PF-00734200，一种有效的竞争性DPP-IV抑制剂，对DPP-IV活性和胰高血糖素样肽-1（GLP-1）在健康成人subjects.Methods动力学的影响DPP-IV抑制：这是一项前瞻性随机，交叉，安慰剂对照，递增，单次，口服剂量研究在临床研究中心进行。27例健康成人受试者随机接受安慰剂或PF-00734200，剂量范围为0.3 - 300 mg（每个剂量组n = 9）。在给药前和给药后不同时间测量药代动力学和药效学终点（DPP-IV活性和GLP-1）。药代动力学（PK）数据表明，药物被迅速吸收，并以双相方式下降。平均最大浓度和浓度曲线下面积似乎随剂量成比例增加。DPP-IV抑制随PF-00734200浓度增加而增加，这可以通过E（max）模型描述，EC 50约为14 ng/ml。与安慰剂相比，DPP-IV抑制导致更高的GLP-1水平蓄积。DPP-IV抑制可增加进餐刺激的血浆GLP-1水平。然而，GLP-1随DPP-IV抑制的增加是非线性的，并且在10 mg时最大化，该剂量导致24小时内约75%加权平均DPP-IV抑制，并且GLP-1相对于安慰剂增加2.3倍。此外，即使在最高PF-00734200剂量水平下，DPP-IV几乎完全抑制超过24 h，与postdinner level.Conclusion相比，GLP-1水平实际上在夜间下降：PF-00734200对DPP-IV的抑制导致血浆GLP-1水平非线性增加，表明GLP-1水平可能受到膳食刺激或生产能力的限制。此外，即使在最大DPP-IV抑制期间，GLP-1水平也下降，表明可能存在除DPP-IV酶降解以外的其他GLP-1消除途径。
Aim: Dipeptidyl peptidase-IV (DPP-IV) inhibitors represent a new promising therapeutic intervention for the treatment of type 2 diabetes mellitus. The aim of this study was to investigate the effects of DPP-IV inhibition by PF-00734200, a potent competitive DPP-IV inhibitor, on the dynamics of DPP-IV activity and glucagon-like peptide-1 (GLP-1) kinetics in healthy adult subjects.Methods: This was a prospective randomized, crossover, placebo-controlled, ascending, single, oral dose study conducted at a clinical research centre. Twenty-seven healthy adult subjects were randomized to receive placebo or PF-00734200 with doses ranging from 0.3 to 300 mg (n = 9 per dose group). Pharmacokinetic and pharmacodynamic end points (DPP-IV activity and GLP-1) were measured prior to, and various times after, dosing.Results: PF-00734200 was well tolerated in all subjects. Pharmacokinetics (PK) data indicate that the drug was rapidly absorbed and declined in a biphasic fashion. Mean maximum concentration and area under concentration curve appeared to increase with doses proportionally. DPP-IV inhibition increased with PF-00734200 concentrations, which can be described by an E(max) model with EC50 approximately being 14 ng/ml. DPP-IV inhibition led to greater GLP-1 level accumulation compared with placebo. Plasma GLP-1 levels stimulated by meals were augmented by DPP-IV inhibition. However, the increase in GLP-1 with DPP-IV inhibition was non-linear and maximized at 10 mg, a dose which resulted in about 75% weighted average DPP-IV inhibition over 24 h and a 2.3-fold increase in GLP-1 over placebo. Moreover, even with near complete inhibition of DPP-IV for over 24 h at the highest PF-00734200 dose levels, the GLP-1 levels actually declined during the night compared with postdinner levels.Conclusion: DPP-IV inhibition by PF-00734200 resulted in a non-linear increase in plasma GLP-1 level, suggesting GLP-1 levels may be limited by meal stimulus or by production capacity. In addition, GLP-1 level declined even during maximal DPP-IV inhibition, suggesting that there may be additional pathways of GLP-1 elimination other than DPP-IV enzymatic breakdown.