A dual PPAR α/γ agonist increases adiponectin and improves plasma lipid profiles in healthy subjects

被引：15

作者：

Decochez K. ^{[1
]}

Rippley R.K. ^{[2
]}

Miller J.L. ^{[3
]}

De Smet M. ^{[4
]}

Yan K.X. ^{[2
]}

Matthijs Z. ^{[1
]}

Riffel K.A. ^{[2
]}

Song H. ^{[2
]}

Zhu H. ^{[3
]}

Maynor H.O. ^{[3
]}

Tanaka W. ^{[3
]}

Johnson-Levonas A.O. ^{[3
]}

Davies M.J. ^{[3
]}

Gottesdiener K.M. ^{[3
]}

Keymeulen B. ^{[1
]}

Wagner J.A. ^{[3
,5
]}

机构：

[1] Department of Endocrinology, Academic Hospital, Brussels Free University - VUB, Brussels

[2] Merck and Co Inc., West Point, PA

[3] Merck and Co Inc., Rahway, NJ

[4] Merck, Sharpe and Dohme, Brussels

[5] Department of Clinical Pharmacology, Merck Research Laboratories, RY33-664, Rahway, NJ 07065

来源：

Drugs in R&D | 2006年 / 7卷 / 2期

关键词：

Free Fatty Acid; Rosiglitazone; Pioglitazone; Multiple Dose; Fenofibrate;

D O I：

10.2165/00126839-200607020-00004

中图分类号：

学科分类号：

摘要：

Background: The objective of these studies was to evaluate the pharmacokinetics and pharmacodynamics of MK-0767, a prototypical dual peroxisome proliferator-activated receptor (PPAR) α/γ agonist, following administration of single and multiple oral doses in healthy male subjects. Methods: The first study was a double-blind, randomised, placebo-controlled, alternating two-panel, rising dose protocol in which single doses of 1-80mg of MK-0767 were administered. The second study was a double-blind, randomised, placebo-controlled, staggered incremental dose, parallel-group protocol in which multiple doses of 0.3-25mg of MK-0767 were administered once daily for 14 days. In both studies at each dose level, six subjects received MK-0767 and two subjects received placebo. Results: Plasma area under the concentration-time curve and maximum plasma concentration increased with single and multiple doses of MK-0767 over the dose ranges studied. The apparent terminal half-life of MK-0767 averaged ∼36 hours following single and multiple doses. Steady-state plasma concentrations were achieved following ∼8 days of multiple doses. Compared with placebo, MK-0767 produced dose-dependent reductions in triglycerides (-26 ± 8% [p = 0.002] and -33 ± 13% [p = 0.008]) and free fatty acids (-50 ± 11% [p < 0.001] and -67 ± 23% [p = 0.008]) following single and multiple doses, respectively. Significant (p ≤ 0.050) dose-dependent alterations in adiponectin (332 ± 36%), low-density lipoprotein cholesterol (-29 ± 5%), total cholesterol (-19 ± 3%), non-high-density lipoprotein cholesterol (-28 ± 4%), and fasting plasma glucose (-6 ± 2%; only in the 25mg group) were observed after multiple doses. Conclusions: The observed effects of MK-0767 on adiponectin, free fatty acids and lipids, even after single doses, demonstrate that this prototypical dual PPAR α/γ agonist has clinically meaningful activity in vivo. © 2006 Adis Data Information BV. All rights reserved.

引用

页码：99 / 110

页数：11

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