Dai Haiqinq, Gustavson Stephanie M, Preston Gregory M, Eskra James D, Calle Roberto, Hirshberg Boaz
Department of Cardiovascular and Metabolic Diseases, Pfizer Inc., Groton, CT 06340, USA.
Diabetes Obes Metab. 2008 Jun;10(6):506-13. doi: 10.1111/j.1463-1326.2007.00742.x. Epub 2008 Feb 18.
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.
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.
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.
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.
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景的治疗手段。本研究的目的是调查强效竞争性DPP-IV抑制剂PF-00734200抑制DPP-IV对健康成年受试者DPP-IV活性动态及胰高血糖素样肽-1（GLP-1）动力学的影响。
这是一项在临床研究中心进行的前瞻性随机、交叉、安慰剂对照、剂量递增、单次口服给药研究。27名健康成年受试者被随机分为接受安慰剂或PF-00734200，剂量范围为0.3至300毫克（每组9人）。在给药前及给药后不同时间测量药代动力学和药效学终点指标（DPP-IV活性和GLP-1）。
所有受试者对PF-00734200耐受性良好。药代动力学（PK）数据表明该药物吸收迅速，呈双相下降。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抑制作用随PF-00734200浓度增加，可用E(max)模型描述，EC50约为14纳克/毫升。与安慰剂相比，DPP-IV抑制导致更高的GLP-1水平蓄积。进餐刺激的血浆GLP-1水平因DPP-IV抑制而升高。然而，DPP-IV抑制导致的GLP-1升高是非线性的，在10毫克剂量时达到最大，该剂量在24小时内导致约75%的加权平均DPP-IV抑制，GLP-1水平比安慰剂升高2.3倍。此外，即使在最高PF-00734200剂量水平下DPP-IV被近乎完全抑制超过24小时，与晚餐后水平相比，夜间GLP-1水平实际上仍下降。
PF-00734200抑制DPP-IV导致血浆GLP-1水平呈非线性增加，提示GLP-1水平可能受进餐刺激或产生能力限制。此外，即使在最大程度抑制DPP-IV期间GLP-1水平仍下降，提示除DPP-IV酶促降解外可能存在其他GLP-1消除途径。
