search
for
 About Bioline  All Journals  Testimonials  Membership  News


Indian Journal of Pharmacology
Medknow Publications on behalf of Indian Pharmacological Society
ISSN: 0253-7613
EISSN: 0253-7613
Vol. 42, No. 4, 2010, pp. 229-233
Bioline Code: ph10065
Full paper language: English
Document type: Research Article
Document available free of charge

Indian Journal of Pharmacology, Vol. 42, No. 4, 2010, pp. 229-233

 en Nature of action of sitagliptin, the dipeptidyl peptidase-IV inhibitor in diabetic animals
Davis, Joseph A.; Singh, Shuchita; Sethi, Sachin; Roy, Subhasis; Mittra, Shivani; Rayasam, Geetavani; Bansal, Vinay; Sattigeri, Jitendra & Ray, Abhijit

Abstract

Objective : The aim of this study was to evaluate the dipeptidyl peptidase-IV (DPP-IV) inhibitor sitagliptin with respect to mode of inhibition and its in vivo duration of inhibition and efficacy in type 2 diabetes animal model.
Materials and Methods : DPP-IV enzyme assay was carried out in human plasma (10 μL) or human recombinant enzyme (10 ng) using H-Gly-Pro-AMC as a substrate. The competitive nature was estimated by plotting IC 50 values measured at different substrate concentrations on the Y axis and substrate concentration on the X axis. The tight binding nature was estimated by plotting IC 50 values measured at different plasma volumes on the Y axis and plasma volumes on the X axis. Fast binding kinetics was assessed by progressive curves at different inhibitor concentrations in the DPP-IV assay. The reversibility of the inhibitor was assessed by a dissociation study of the DPP-IV-sitagliptin complex. Durations of DPP-IV inhibition and efficacy were shown in ob/ob mice dosed at 10 mg/kg, p.o.
Results : Sitagliptin is a competitive, reversible, fast and tight binding DPP-IV inhibitor. In ob/ob mice, 10 mg/kg, (p.o.) showed a long duration of inhibition of > 70% at 8 h. The duration was translated into long duration of efficacy (~ 35% glucose excursion at 8 h) in the same model and the effect was comparable to vildagliptin.
Conclusion : The DPP-IV inhibitor sitagliptin behaves as a competitive, tight, and fast binding inhibitor. Sitagliptin differs mechanistically from vildagliptin and exhibits comparable efficacy to that of latter. The finding may give an understanding to develop-second generation DPP-IV inhibitors with desired kinetic profiles.

Keywords
Dipeptidyl peptidase-IV, fast binding inhibitor, sitagliptin, type 2 diabetes mellitus, vildagliptin

 
© Copyright 2010 Indian Journal of Pharmacology.
Alternative site location: http://www.ijp-online.com

Home Faq Resources Email Bioline
© Bioline International, 1989 - 2024, Site last up-dated on 01-Sep-2022.
Site created and maintained by the Reference Center on Environmental Information, CRIA, Brazil
System hosted by the Google Cloud Platform, GCP, Brazil