title: The relationship between anagliptin concentration showing over 80% inhibition of plasma dipeptidyl peptidase-4 activity and its protective effect against glucagon-like peptide-1 degradation.
abstract: In dipeptidyl peptidase-4 (DPP-4) inhibitors, the inhibition of plasma DPP-4 activity by 80% is considered sufficient to have an effect on glycemic control improvement through the elevation of intact glucagon-like peptide-1 (GLP-1). To clarify whether or not the 80% inhibition is sufficient to protect against GLP-1 degradation, we investigated rats with a continuous infusion of exogenous GLP-1. When GLP-1 was infused into the femoral or portal vein, the steady state active GLP-1 levels in plasma significantly increased (P<0.05) at the 80% inhibitory concentration (IC80) of anagliptin (a highly selective DPP-4 inhibitor) against plasma DPP-4 activity, compared with control. In addition, the peptide levels increased in a concentration-dependent manner at drug concentrations from IC80 to 10-fold IC80, and the levels at the 10-fold IC80 were significantly higher (P<0.05) than those at IC80. The concentration dependency on GLP-1 increment was also confirmed based on the experiment in which the endogenous active GLP-1 levels were measured after an oral carbohydrate load. These findings suggest that an almost complete inhibition (80%) of plasma DPP-4 activity was insufficient to protect GLP-1 degradation, and much higher drug concentrations such as 10-fold IC80 are necessary to potently protect GLP-1 from degradation by DPP-4 commonly present in blood and tissues.
authors: Sanwa Kagaku Kenkyusho, Co. Ltd, Pharmaceutical Research Laboratories, Mie, Japan.
authors: S
authors: S
authors: Furuta
authors: Sanwa Kagaku Kenkyusho, Co. Ltd, Pharmaceutical Research Laboratories, Mie, Japan.
authors: M
authors: M
authors: Goto
authors: Sanwa Kagaku Kenkyusho, Co. Ltd, Pharmaceutical Research Laboratories, Mie, Japan.
authors: M
authors: M
authors: Tamura
authors: Sanwa Kagaku Kenkyusho, Co. Ltd, Pharmaceutical Research Laboratories, Mie, Japan.
authors: S
authors: S
authors: Yamashita
authors: Sanwa Kagaku Kenkyusho, Co. Ltd, Pharmaceutical Research Laboratories, Mie, Japan.
authors: K
authors: K
authors: Nakaya
authors: Sanwa Kagaku Kenkyusho, Co. Ltd, Pharmaceutical Research Laboratories, Mie, Japan.
authors: Y
authors: Y
authors: Furuta
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002241:Carbohydrates / Q000008:administration & dosage; D018819:Dipeptidyl Peptidase 4 / Q000187:drug effects / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005268:Femoral Vein; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage / Q000097:blood*; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D011169:Portal Vein; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D001786:Blood Glucose; D002241:Carbohydrates; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D011743:Pyrimidines; D052216:Glucagon-Like Peptide 1; D018819:Dipeptidyl Peptidase 4; C583175:anagliptin