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The Effect of Food on the Oral Bioavailability and the Pharmacodynamic Actions of the Insulinotropic Agent Nateglinide in Healthy Subjects
Author(s) -
Karara Adel H.,
Dunning Beth E.,
McLeod James F.
Publication year - 1999
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/00912709922007606
Subject(s) - nateglinide , bioavailability , cmax , crossover study , meal , pharmacokinetics , medicine , pharmacology , pharmacodynamics , postprandial , area under the curve , insulin , oral administration , chemistry , endocrinology , diabetes mellitus , type 2 diabetes , placebo , alternative medicine , pathology
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 under fasting 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 C max and 52% decrease in t max ), 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 C max and a 22% increase in t max 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 C max ; both t max 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.