Nateglinide (
Starlix,
SDZ DJN 608 or
A-4166), a new insulinotropic agent, is intended to be administered prior to a meal in order to improve early
insulin release in
non-insulin-dependent diabetes mellitus patients. The effects of a meal on the oral bioavailability and pharmacodynamic actions of
nateglinide were investigated. Twelve healthy male subjects completed this randomized, single-dose, four-way crossover study in which each subject received a 60 mg dose of
nateglinide 10 minutes before the start of and immediately after a high-fat breakfast meal. In addition, each subject received a single 30 and 60 mg dose of
nateglinide underfasting conditions. Plasma and urine concentrations of
nateglinide were determined by an HPLC method while plasma
glucose and
insulin concentrations were measured by standard immunoassay methods. Compared to the fasted state, administration of
nateglinide 10 minutes before the meal was associated with an increase in the rate of absorption (12% increase in Cmax and 52% decrease in tmax), while there was no significant effect on the extent of absorption (AUC). Alternatively, when
nateglinide was given after the meal, a food effect was observed that was characterized by a decrease in the rate of absorption: 34% decrease in Cmax and a 22% increase in tmax but no significant effect on AUC.
Nateglinide was rapidly eliminated with plasma t 1/2 = 1.4 hours. Its plasma renal clearance, 20.7 ml/min, appears to be due mostly to active tubular secretion. However, only 13% to 14% of the dose is recovered as
nateglinide in the urine. The 30 and 60 mg
tablets were dose proportional in terms of both AUC and Cmax; both tmax and t 1/2 were dose independent. Regardless of timing, the combination of a meal and
nateglinide produced a larger increase in
insulin levels than did
nateglinide alone. Meal-related
glucose excursions were eliminated when
nateglinide was taken prior to the meal. Thus, the rapid onset/short duration stimulation of
insulin release by
nateglinide should allow good control of prandial
hyperglycemia while limiting exposure to
hyperinsulinemia.