RT Journal Article SR Electronic T1 Pharmacokinetic and Pharmacodynamic Properties of the Glucokinase Activator MK-0941 in Rodent Models of Type 2 Diabetes and Healthy Dogs JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP mol.111.074401 DO 10.1124/mol.111.074401 A1 Jun-ichi Eiki A1 Yasufumi Nagata A1 Mayumi Futamura A1 Kaori Sasaki-Yamamoto A1 Tomoharu Iino A1 Teruyuki Nishimura A1 Masato Chiba A1 Sumika Ohyama A1 Riki Yoshida-Yoshimoto A1 Kenji Fujii A1 Hideka Hosaka A1 Hiroko Goto-Shimazaki A1 Akito Kadotani A1 Tomoyuki Ohe A1 Songnian Lin A1 Ronald B. Langdon A1 Joel P. Berger YR 2011 UL http://molpharm.aspetjournals.org/content/early/2011/09/21/mol.111.074401.abstract AB Glucokinase activators (GKAs) are small-molecule agents that enhance glucose sensing by pancreatic â-cells and glucose metabolism by hepatocytes. There is strong interest in these agents as potential therapies for type 2 diabetes. Here, we report key pharmacokinetic and pharmacodynamic findings from preclinical studies of the GKA MK-0941. Incubated in vitro with recombinant human glucokinase, 1 μM MK-0941 lowered the S0.5 of this enzyme for glucose from 6.9 to 1.4 mM and increased the maximum velocity of glucose phosphorylation by 1.5-fold. In 2.5 and 10 mM glucose, the EC50 values for activation of GK by MK-0941 were 0.240 and 0.065 μM, respectively. Treatment of isolated rat islets of Langerhans and hepatocytes with 10 μM MK-0941 increased insulin secretion by 17-fold and glucose uptake up to 18-fold, respectively. MK-0941 exhibited strong glucose-lowering activity in C57BL/6J mice maintained on a high-fat diet (HFD), db/db mice, HFD plus low-dose streptozotocin-treated mice, and non-diabetic dogs. In both mice and dogs, oral doses of MK-0941 were rapidly absorbed and rapidly cleared from the blood; plasma levels reached maximum within 1 h and fell thereafter with a half-life of ~2 h. During oral glucose tolerance testing in dogs, MK-0941 reduced total area-under-the-curve post-challenge (0–2 h) plasma glucose levels by up to 48%, compared with vehicle-treated controls. When administered twice-daily to mice for 16 days, and once-daily to the dog for 4 days, MK-0941 remained efficacious on successive days. These findings support further investigation of MK-0941 as a potential therapeutic agent for treatment of type 2 diabetes.