A dual PPAR alpha/gamma agonist increases adiponectin and improves plasma lipid profiles in healthy subjects.
BACKGROUND
The objective of these studies was to evaluate the pharmacokinetics and pharmacodynamics of MK-0767, a prototypical dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma 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 1-80 mg 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 0.3-25 mg 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 approximately 36 hours following single and multiple doses. Steady-state plasma concentrations were achieved following approximately 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 < or = 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 25 mg 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 alpha/gamma agonist has clinically meaningful activity in vivo.
Diabetes Unit, Department of Endocrinology, Academic Hospital, Brussels Free University - VUB, Brussels, Belgium.
Katelijn
K
Decochez
Ronda K
RK
Rippley
Jutta L
JL
Miller
Marina
M
De Smet
Kerri X
KX
Yan
Zissi
Z
Matthijs
Kerry A
KA
Riffel
Hengchang
H
Song
Haiyuan
H
Zhu
Hannah O
HO
Maynor
Wesley
W
Tanaka
Amy O
AO
Johnson-Levonas
Michael J
MJ
Davies
Keith M
KM
Gottesdiener
Bart
B
Keymeulen
John A
JA
Wagner
D052242:Adiponectin / Q000097:blood*; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001786:Blood Glucose / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005221:Fatigue / Q000139:chemically induced; D005230:Fatty Acids, Nonesterified / Q000097:blood; D006261:Headache / Q000139:chemically induced; D006801:Humans; D000960:Hypolipidemic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D007328:Insulin / Q000097:blood; D008055:Lipids / Q000097:blood*; D008297:Male; D008875:Middle Aged; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D013844:Thiazoles / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood
D052242:Adiponectin; D001786:Blood Glucose; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D005230:Fatty Acids, Nonesterified; D000960:Hypolipidemic Agents; D007328:Insulin; D008055:Lipids; C487303:MK0767; D047493:PPAR alpha; D047495:PPAR gamma; D013844:Thiazoles; D014280:Triglycerides; D002784:Cholesterol