Comparison of the rapidity of onset of the therapeutic effect between nateglinide and mitiglinide by PK/PD analysis in rats

Abstract

Nateglinide and mitiglinide are immediate short-acting insulinotropic agents. Both are administered preprandially to control postprandial hyperglycemia. Glinide drugs are characterized by immediate onset as well as rapid disappearance of effect as compared with sulfonylurea drugs. We examined the rapidity of onset of the therapeutic effect between nateglinide and mitiglinide by pharmacokinetic/pharmacodynamic analysis using the receptor-binding-dissociation model in rats. Nateglinide or mitiglinide was administered orally or intravenously to rats and blood samples were collected at various time-points post administration. The plasma concentrations of the unbound drug forms and the blood glucose were measured. When the simultaneous fitting of oral administration and intravenous administration was performed using the receptor-binding-dissociation model, the measured values exhibited good correspondence with the fitting curve. Moreover, the time-courses of changes of the receptor-binding rate (sulfonylurea receptor) were examined using the parameters (k (on): second-order binding association constant to the receptor, Φ: receptor-binding occupancy ratio) obtained from the analysis. The results showed that the binding rate, which is important for glinide drugs in the early phase after administration, was obviously higher for nateglinide than that for mitiglinide from 10 min after oral administration and between 0 and 30 min after intravenous administration. These results suggest a more rapid onset of the therapeutic effect of nateglinide than that of mitiglinide after the drug is distributed into the blood.

Pharmacokinetic and pharmacodynamic modeling of oral mitiglinide on glucose lowering in healthy Chinese volunteers

“…Toshiyuki Takanohashi et al reported the pk-pd. modeling methodology to describe the rapidity therapeutic effect of mitiglinide by using the receptor-binding-dissociation in rats [12]. However, model of inhaled glucose in healthy humans has not been published previously.…”

“…Plasma mitiglinide concentration was determined by the modification of the methods of Yu and Takanohashi [9, 12]. A 1200 HPLC system (Agilent technologies, Palo Alto, CA, USA) coupled with a triple-quadrupole tandem API 4000 mass spectrometer (AB/MDS-Sciex, Concord, Ontario, Canada) were used for analysis.…”