Pharmacokinetic and pharmacodynamic properties of the glucokinase activator MK-0941 in rodent models of type 2 diabetes and healthy dogs

Jun Ichi Eiki, Yasufumi Nagata, Mayumi Futamura, Kaori Sasaki-Yamamoto, Tomoharu Iino, Teruyuki Nishimura, Masato Chiba, Sumika Ohyama, Riki Yoshida-Yoshimioto, Kenji Fujii, Hideka Hosaka, Hiroko Goto-Shimazaki, Akito Kadotani, Tomoyuki Ohe, Songnian Lin, Ronald B. Langdon, Joel P. Berger

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Glucokinase activators (GKAs) are small-molecule agents that enhance glucose sensing by pancreatic β 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 3-[[6-(ethylsulfonyl)-3-pyridinyl] oxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1Hpyrazol-3-yl)benzamide (MK-0941). Incubated in vitro with recombinant human glucokinase, 1 μM MK-0941 lowered the S 0.5 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 EC 50 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 nondiabetic 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 postchallenge (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.

Original languageEnglish
Pages (from-to)1156-1165
Number of pages10
JournalMolecular Pharmacology
Volume80
Issue number6
DOIs
Publication statusPublished - 2011 Dec
Externally publishedYes

Fingerprint

Glucokinase
Type 2 Diabetes Mellitus
Rodentia
Pharmacokinetics
Dogs
Glucose
High Fat Diet
Hepatocytes
3-((6-(ethylsulfonyl)-3-pyridinyl)oxy)-5-(2-hydroxy-1-methylethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide
Glucose Tolerance Test
Streptozocin
Islets of Langerhans
Inbred C57BL Mouse
Area Under Curve
Half-Life
Phosphorylation
Insulin

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Eiki, J. I., Nagata, Y., Futamura, M., Sasaki-Yamamoto, K., Iino, T., Nishimura, T., ... Berger, J. P. (2011). Pharmacokinetic and pharmacodynamic properties of the glucokinase activator MK-0941 in rodent models of type 2 diabetes and healthy dogs. Molecular Pharmacology, 80(6), 1156-1165. https://doi.org/10.1124/mol.111.074401

Pharmacokinetic and pharmacodynamic properties of the glucokinase activator MK-0941 in rodent models of type 2 diabetes and healthy dogs. / Eiki, Jun Ichi; Nagata, Yasufumi; Futamura, Mayumi; Sasaki-Yamamoto, Kaori; Iino, Tomoharu; Nishimura, Teruyuki; Chiba, Masato; Ohyama, Sumika; Yoshida-Yoshimioto, Riki; Fujii, Kenji; Hosaka, Hideka; Goto-Shimazaki, Hiroko; Kadotani, Akito; Ohe, Tomoyuki; Lin, Songnian; Langdon, Ronald B.; Berger, Joel P.

In: Molecular Pharmacology, Vol. 80, No. 6, 12.2011, p. 1156-1165.

Research output: Contribution to journalArticle

Eiki, JI, Nagata, Y, Futamura, M, Sasaki-Yamamoto, K, Iino, T, Nishimura, T, Chiba, M, Ohyama, S, Yoshida-Yoshimioto, R, Fujii, K, Hosaka, H, Goto-Shimazaki, H, Kadotani, A, Ohe, T, Lin, S, Langdon, RB & Berger, JP 2011, 'Pharmacokinetic and pharmacodynamic properties of the glucokinase activator MK-0941 in rodent models of type 2 diabetes and healthy dogs', Molecular Pharmacology, vol. 80, no. 6, pp. 1156-1165. https://doi.org/10.1124/mol.111.074401
Eiki, Jun Ichi ; Nagata, Yasufumi ; Futamura, Mayumi ; Sasaki-Yamamoto, Kaori ; Iino, Tomoharu ; Nishimura, Teruyuki ; Chiba, Masato ; Ohyama, Sumika ; Yoshida-Yoshimioto, Riki ; Fujii, Kenji ; Hosaka, Hideka ; Goto-Shimazaki, Hiroko ; Kadotani, Akito ; Ohe, Tomoyuki ; Lin, Songnian ; Langdon, Ronald B. ; Berger, Joel P. / Pharmacokinetic and pharmacodynamic properties of the glucokinase activator MK-0941 in rodent models of type 2 diabetes and healthy dogs. In: Molecular Pharmacology. 2011 ; Vol. 80, No. 6. pp. 1156-1165.
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