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PubMedDate not supplied

Clinical characteristics of nateglinide response as assessed by insulinogenic indices: preliminary study to determine an optimal indication for nateglinide.

Insulin secretion dynamics and response to nateglinide were studied in patients with type 2 diabetes and reduced early-phase insulin secretion. On day 1, 24 patients underwent a 75-g oral glucose tolerance test without taking nateglinide. On day 2, they were given oral nateglinide 90 mg immediately before the oral glucose tolerance test. After glucose loading, insulin levels increased significantly at 30, 60, 90, and 120 minutes after the patients took nateglinide, along with insulinogenic indices, the total area under the insulin curve, the area under the 0- to 90-minute insulin curve, and the area under the 90- to 180-minute insulin curve. Both the plasma glucose level at 60, 90, 120, and 180 minutes and the total area under the glucose curve were significantly reduced following nateglinide administration. Compared with the low responders (n=13), the high responders (n=11) had a significantly shorter duration of disease, significantly higher insulinogenic indices in the absence of nateglinide administration, and a higher homeostasis model assessment-beta cell performance. Nateglinide demonstrated a rapid-onset and rapid-offset insulin secretion-stimulating effect in this study population. A single dose of nateglinide may be indicated for patients with a relatively high homeostasis model assessment-beta cell performance, a short duration of disease, and relatively high insulinogenic indices prior to nateglinide administration.

Administration, Oral↗

PubMed2002

The effects of nateglinide following oral glucose load in impaired glucose tolerance subjects: rapid insulin stimulation by nateglinide in IGT subjects.

This study was designed to determine the effect of a novel insulin secretagogue, nateglinide, on the glycemic response curve and early insulin secretion following oral glucose load in impaired glucose tolerance (IGT) subjects. Thirteen subjects were given a 75 g oral glucose tolerance test (75 g OGTT), the findings of which resulted in the diagnosis of IGT. The subjects returned to our hospital immediately. Eight subjects, in whom neither body weight nor life style (daily diet and exercise) was significantly altered during this period, were given 90 mg of nateglinide 5 min before a second oral glucose load in order to examine restoration of impaired early insulin secretion. Nateglinide administration resulted in the almost normalization of the glycemic response curve with restoration of impairment in early insulin response at 30 and 60 min after an oral glucose load. The area under the secreted insulin-time curve was not changed significantly by nateglinide administration. A single dose of nateglinide was shown to almost normalize the glycemic response curve after a 75 g OGTT and to restore impairment in early insulin response in IGT subjects.

Area Under Curve↗

PubMed2006

Effect of decrease in both postprandial blood glucose (PBG) and fasting blood glucose (FBG) levels in normal beagle dogs with nateglinide enteric coated granules and immediate release tablets.

Nateglinide is a new quick action/short duration (QRSD) type of oral blood glucose regulator, and nateglinide immediate release tablets are used for patients with mild diabetes under the trade name of Fastic((R)) tablets. In this study, we attempted to determine if it was possible to control both post-prandial blood glucose level (PBG) and fasting blood glucose level (FBG) for moderate or severe diabetes through controlled release of nateglinide. Enteric coated granules were selected for the administration form for controlled release of nateglinide, and three types of enteric coated granules were prepared having dissolution pH values of 5.5, 6.5 and 7.2. The three types of enteric coated granules were each administered separately or the enteric coated granules having an dissolution pH of 6.5 were administered simultaneous to administration of nateglinide immediate release tablets to normal beagle dogs just before feeding followed by measurement of plasma nateglinide concentration, plasma insulin concentration and blood glucose level. In the case of administering enteric coated granules alone (nateglinide: 9 mg/kg), the absorption of nateglinide was confirmed to tend to be delayed as the dissolution pH increased. In the case of an dissolution pH of 5.5, decreases in both PBG and FBG were observed. In the case of dissolution pH values of 6.5 and 7.2, only decrease in FBG was observed. In case of nateglinide immediate release tablets (nateglinide: 9 mg/kg), only decrease in PBG was observed. Decreases in both PBG and FBG were observed in the case of simultaneous administration of dissolution pH 6.5 enteric coated granules and nateglinide immediate release tablets just before feeding (nateglinide: 90 mg/head+60 mg/head). A correlation was observed between plasma nateglinide concentrations and blood glucose levels. On the other hand, there were no correlations observed between changes in plasma insulin concentrations and blood glucose levels. In case of nateglinide immediate release tablets (nateglinide: 150 mg/head), Decreases in both PBG and FBG were observed. However, the nateglinide controlled release formulation is more useful than the nateglinide immediate release tablets from the view point of avoidance of side effect, or of easy control of both PBG and FBG. On the basis of these results, the design of a controlled release formulation that contains nateglinide was suggested to enable control of both PBG and FBG for moderate and severe diabetes patients.

Administration, Oral↗

PubMed2001

Nateglinide: A structurally novel, short-acting, hypoglycemic agent.

Nateglinide is a short-acting, pancreatic, beta-cell-selective, K(ATP) potassium channel blocker that improves overall glycemic control in type 2 diabetes. Although nateglinide's mechanism of action is related to that of sulphonyl-ureas and repaglinide, important differences do exist. Nateglinide binds rapidly to the sulfonylurea SUR1 receptor with a relatively low affinity, and it dissociates from it extremely rapidly in a manner of seconds. This rapid association and dissociation gives nateglinide a unique "fast on-fast off" effect. Thus, nateglinide has a rapid onset and short duration of action stimulating insulin secretion in vivo and providing good control of postprandial hyperglycemia when taken immediately prior to meals. The rapid action of nateglinide on the beta cells stimulates and restores the normal physiological first and early phase of insulin secretion, consequently reducing postprandial hyperglycemia. This hypoglycemic effect of nateglinide leads to improved glycemic control, while the short duration avoids delayed hyperinsulinemia and hypoglycemia after meals. Nateglinide is not a sulfonylurea, but it shares the mechanism of action of commonly used oral hypoglycemic agents such as glibenclamide and glipizide. Like the recently introduced, short-acting agent, repaglinide, it does not incorporate a sulfonylurea moiety. However, nateglinide's effects on insulin secretion and glycemic control differ significantly from the sulfonylureas and repaglinide in that it preferentially stimulates acute phase insulin, better controls postprandial glucose excursions and spikes, and causes less hyperinsulinemia and hypoglycemia. Compounds with such a profile should not only achieve improved overall glucose control, but also reduce the risk of vascular complications which is the most important feature of nateglinide. Clinical studies with nateglinide have confirmed that it acts rapidly and both restores insulin release and attenuates the postprandial glucose spike. Nateglinide is both effective and well tolerated in the treatment of type 2 diabetes. The reported overall profile of adverse effects appears to be superior to that of other K(ATP) potassium channel blockers, the glucose modulator metformin and PPARgamma agonists such as troglitazone. Clinical comparisons of these agents have shown nateglinide to be more effective in attenuating postprandial glucose than any other oral hypoglycemic agent, and that treatment with both nateglinide and metformin provides additive effects that afford improved control of plasma glucose levels. The administration regimen for nateglinide, immediately prior to meals, also facilitates patient compliance. (c) 2001 Prous Science. All rights reserved.

Journal Article↗

PubMed2003

The effect of nateglinide taken with food on gastric emptying rates in healthy subjects.

OBJECTIVES: The aim of this study was to determine the effect of the timing of food intake on the pharmacokinetics and pharmacodynamics of oral nateglinide 60 mg and the effect of nateglinide on the rate of gastric emptying. METHODS: A randomized, double-blind, placebo-controlled, single-dose, 6-period, crossover study conducted in healthy male volunteers aged 18 to 50 years. On 5 occasions, subjects received a single 60-mg tablet of nateglinide at -30, -10, -5, -1, or 40 minutes from the start of a standard metal. Treatment blind was maintained by administration of placebo tablets at all other time points. On the sixth occasion, subjects received placebo tablets at all dosing time points. Each subject received acetaminophen 1 g at the beginning of the standard breakfast on each treatment day as an indicator of the rate of gastric emptying. Plasma samples were collected over a 6-hour period to determine nateglinide, glucose, insulin, and acetaminophen concentrations. RESULTS: Twelve white men with a mean (SD) age of 30 (6.8) years (range, 21-47 years) and mean (SD) weight of 73.3 (11.0) kg completed all 6 periods of the study. Nateglinide absorption was faster when administered at -5 or -10 minutes relative to food, as characterized by higher nateglinide area under the concentration-time curve from 0 to 5 hours (AUC(0-5)) and maximum plasma concentration (C(max)) values, compared with those observed at other dosing time points. Mean time to C(max) (T(max)) was also shorter when nateglinide was given at -10 minutes versus other dosing time points. Mean nateglinide half-life was similar for all 5 treatments (range, 81.3-94.6 minutes). The overall treatment effect was statistically significant for nateglinide AUC(0-5) (P = 0.031), C(max) (P = 0.001), and T(max) (P < 0.001). Insulin T(max) was shorter after nateglinide administration at -30 or -10 minutes, which was associated with lower glucose C(max) values (-30 minutes, P < 0.05) and a tendency for lower glucose AUC(0-5) values (-10 minutes, P = NS). NS). No treatment effects were observed for any of the acetaminophen indices, as demonstrated by the absence of any change in acetaminophen T(max) or C(max) value. CONCLUSIONS: Nateglinide was well tolerated and no treatment-limiting adverse events were reported in the population studied. Nateglinide administration appeared to have no effect on the rate of gastric emptying as indicated by acetaminophen indices, regardless of the time of nateglinide administration. The findings imply that the time for nateglinide administration to obtain optimal pharmacodynamic effects is prior to food consumption.

Adult↗

PubMed1999

The effect of food on the oral bioavailability and the pharmacodynamic actions of the insulinotropic agent nateglinide in healthy subjects.

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.

Administration, Oral↗

PubMed2004

Acute and long-term effects of nateglinide on insulin secretory pathways.

Acute and chronic effects of the insulinotropic drug nateglinide upon insulin release were examined in the BRIN-BD11 cell line. Nateglinide (10-400 microm) stimulated a concentration-dependent increase (P<0.05-P<0.001) in insulin release at a non-stimulatory (1.1 mm) glucose concentration. The insulinotropic response to 200 microm nateglinide was increased at 30 mm (P<0.01), but not 5.6-16.7 mm glucose concentrations. In depolarized cells, nateglinide (50-200 microm) evoked K(ATP) channel-independent insulin secretion (P<0.05-P<0.001) in the absence and presence of 5.6-30.0 mm glucose (P<0.001). Exposure for 18 h to 100 microm nateglinide abolished the acute insulinotropic effects of 200 microm nateglinide, tolbutamide or glibenclamide, but had no effect upon the insulinotropic effect of 200 microm efaroxan. While 18 h exposure to 100 microm nateglinide did not affect basal insulin release or insulin release in the presence of 16.7 mm glucose, 25 microm forskolin or 10 nm PMA, significant inhibition of the insulinotropic effects of 20 mm leucine and 20 mm arginine were observed. These data show that nateglinide stimulates both K(ATP) channel-dependent and-independent insulin secretion. The maintained insulinotropic effects of this drug with increasing glucose concentrations support the antihyperglycaemic actions of nateglinide in Type II diabetes. Studies of the long-term effects of nateglinide indicate that nateglinide shares signalling pathways with sulphonylureas, but not the imidazoline efaroxan. This may be significant when considering a nateglinide treatment regimen, particularly in patients previously treated with sulphonylurea.

Animals↗

PubMed2000

Pancreatic beta-cell K(ATP) channel activity and membrane-binding studies with nateglinide: A comparison with sulfonylureas and repaglinide.

Nateglinide (A-4166) is an amino acid derivative with insulinotrophic action in clinical development for treatment of type 2 diabetes. The aim of this study was to determine whether nateglinide's interaction at the K(ATP) channel/sulfonylurea receptor underlies its more rapid onset and shorter duration of action in animal models. Binding studies were carried out with membranes prepared from RIN-m5F cells and HEK-293 cells expressing recombinant human sulfonylurea receptor 1 (SUR1). The relative order for displacement of [(3)H]glibenclamide in competitive binding experiments with RIN-m5F cell membranes was glibenclamide > glimepiride > repaglinide > glipizide > nateglinide > L-nateglinide > tolbutamide. The results with HEK-293/recombinant human SUR1 cells were similar with the exception that glipizide was more potent than repaglinide. Neither nateglinide nor repaglinide had any effect on the dissociation kinetics for [(3)H]glibenclamide, consistent with both compounds competitively binding to the glibenclamide-binding site on SUR1. Finally, the inability to measure [(3)H]nateglinide binding suggests that nateglinide dissociates rapidly from SUR1. Direct interaction of nateglinide with K(ATP) channels in rat pancreatic beta-cells was investigated with the patch-clamp method. The relative potency for inhibition of the K(ATP) channel was repaglinide > glibenclamide > nateglinide. Kinetics of the inhibitory effect on K(ATP) current showed that the onset of inhibition by nateglinide was comparable to glibenclamide but more rapid than that of repaglinide. The time for reversal of channel inhibition by nateglinide was also faster than with glibenclamide and repaglinide. These results suggest that the unique characteristics of nateglinide are largely the result of its interaction at the K(ATP) channel.

ATP-Binding Cassette Transporters↗

PubMed2004

Repaglinide versus nateglinide monotherapy: a randomized, multicenter study.

OBJECTIVE: A randomized, parallel-group, open-label, multicenter 16-week clinical trial compared efficacy and safety of repaglinide monotherapy and nateglinide monotherapy in type 2 diabetic patients previously treated with diet and exercise. RESEARCH DESIGN AND METHODS: Enrolled patients (n = 150) had received treatment with diet and exercise in the previous 3 months with HbA(1c) >7 and < or =12%. Patients were randomized to receive monotherapy with repaglinide (n = 76) (0.5 mg/meal, maximum dose 4 mg/meal) or nateglinide (n = 74) (60 mg/meal, maximum dose 120 mg/meal) for 16 weeks. Primary and secondary efficacy end points were changes in HbA(1c) and fasting plasma glucose (FPG) values from baseline, respectively. Postprandial glucose, insulin, and glucagon were assessed after a liquid test meal (baseline, week 16). Safety was assessed by incidence of adverse events or hypoglycemia. RESULTS: Mean baseline HbA(1c) values were similar in both groups (8.9%). Final HbA(1c) values were lower for repaglinide monotherapy than nateglinide monotherapy (7.3 vs. 7.9%). Mean final reductions of HbA(1c) were significantly greater for repaglinide monotherapy than nateglinide monotherapy (-1.57 vs. -1.04%; P = 0.002). Mean changes in FPG also demonstrated significantly greater efficacy for repaglinide than nateglinide (-57 vs. -18 mg/dl; P < 0.001). HbA(1c) values <7% were achieved by 54% of repaglinide-treated patients versus 42% for nateglinide. Median final doses were 6.0 mg/day for repaglinide and 360 mg/day for nateglinide. There were 7% of subjects treated with repaglinide (five subjects with one episode each) who had minor hypoglycemic episodes (blood glucose <50 mg/dl) versus 0 patients for nateglinide. Mean weight gain at the end of the study was 1.8 kg in the repaglinide group as compared with 0.7 kg for the nateglinide group. CONCLUSIONS: In patients previously treated with diet and exercise, repaglinide and nateglinide had similar postprandial glycemic effects, but repaglinide monotherapy was significantly more effective than nateglinide monotherapy in reducing HbA(1c) and FPG values after 16 weeks of therapy.

Biomarkers↗

PubMed2004

Effect of a selective CYP2C9 inhibitor on the pharmacokinetics of nateglinide in healthy subjects.

PURPOSE: The objective of the study was to determine the effect of a potent and selective CYP2C9 inhibitor, sulfinpyrazone (Anturane), on the pharmacokinetics of nateglinide (Starlix), a novel antidiabetic drug which is primarily (approximately 70%) metabolized via CYP2C9. METHODS: This was a randomized, open-label, two-period, crossover study in 18 healthy volunteers. Nateglinide was administered as a single 120-mg oral dose alone (reference) on day 1 or in combination with sulfinpyrazone (test) on day 7, following twice-daily 200-mg oral doses (i.e., 400 mg/day) of sulfinpyrazone for 7 days. Pharmacokinetic parameters of nateglinide were determined following the administration of nateglinide alone, and when administered in combination with sulfinpyrazone. Plasma nateglinide concentrations were determined using a validated high-performance liquid chromatography method. RESULTS: The administration of nateglinide in combination with sulfinpyrazone resulted in approximately 28% higher mean AUC of nateglinide (90% CI for test-reference ratio: 1.20-1.39) with no differences in mean peak plasma concentration (Cmax; 90% CI test-reference ratio: 0.86-1.12) compared with nateglinide-alone treatment. The time to reach Cmax (tmax) and the elimination half-life of nateglinide were similar between the two treatments. Both treatments were safe and well tolerated. CONCLUSIONS: Sulfinpyrazone increased the mean exposure of nateglinide by 28% when both drugs were administered in combination. Nateglinide, given as a single dose or co-administered with multiple doses of sulfinpyrazone, was safe and well tolerated in healthy subjects.

Adolescent↗

PubMed2002

Transport and uptake of nateglinide in Caco-2 cells and its inhibitory effect on human monocarboxylate transporter MCT1.

1 Nateglinide, a novel oral hypoglycemic agent, rapidly reaches the maximum serum concentration after oral administration, suggesting that it is rapidly absorbed in the gastrointestinal tract. The aim of this work is to clarify the intestinal absorption mechanism of nateglinide by means of in vitro studies. 2 We examined the transcellular transport and the apical uptake of [(14)C]nateglinide in a human colon carcinoma cell line (Caco-2). We also examined whether nateglinide is transported via monocarboxylate transport-1 (MCT1) by means of an uptake study using MCT1-expressing Xenopus laevis oocytes. 3 In Caco-2 cells, the transcellular transport of [(14)C]nateglinide from the apical to basolateral side was greater than that in the opposite direction. The uptake of [(14)C]nateglinide from the apical side was concentration-dependent, H(+)-dependent, and Na(+)-independent. Kinetic analysis revealed that the Kt and Jmax values of the initial uptake rate of [(14)C]nateglinide were 448 micro M and 43.2 nmol mg protein(-1) 5 min(-1), respectively. Various monocarboxylates, including salicylic acid and valproic acid, and glibenclamide significantly inhibited the uptake of [(14)C]nateglinide. 4 The uptake study using MCT1-expressing oocytes showed that nateglinide inhibits the MCT1-mediated uptake of [(14)C]L-lactic acid, though nateglinide itself is not transported by MCT1. 5 Taken together, these results suggest that the uptake of nateglinide from the apical membranes of Caco-2 cells is, at least in part, mediated by a proton-dependent transport system(s) distinct from MCT1.

Administration, Oral↗

PubMed2006

Comparison of nateglinide and gliclazide in combination with metformin, for treatment of patients with Type 2 diabetes mellitus inadequately controlled on maximum doses of metformin alone.

AIM: To compare the effects of nateglinide plus metformin with gliclazide plus metformin on glycaemic control in patients with Type 2 diabetes. METHODS: Double-blind, double-dummy, parallel group, randomized, multicentre study over 24 weeks. Patients with inadequate glucose control on maximal doses of metformin were randomized to additionally receive nateglinide (n = 133) or gliclazide (n = 129). Changes from baseline in HbA1c, fasting plasma glucose (FPG) and mealtime glucose and insulin excursions were examined. RESULTS: HbA1c was significantly (P < 0.001) decreased from baseline in both treatment groups (mean changes: nateglinide -0.41%, gliclazide -0.57%), but with no significant difference between treatments. Proportions of patients achieving a reduction of HbA1c >or= 0.5% or an end point HbA1c < 7% were also similar (nateglinide 58.1%, gliclazide 60.2%). Changes from baseline in FPG were similarly significant in both treatment groups (nateglinide -0.63, gliclazide -0.82 mmol/l). Reduction from baseline in maximum postprandial glucose excursion were significant in the nateglinide group only (nateglinide -0.71, gliclazide -0.10 mmol/l; P = 0.037 for difference). Postprandial insulin levels were significantly higher with nateglinide compared with gliclazide. The overall rate of hypoglycaemia events was similar in the nateglinide group compared with the gliclazide group. CONCLUSIONS: No significant difference was seen between nateglinide plus metformin and gliclazide plus metformin in terms of HbA1c. However, the nateglinide combination demonstrated better postprandial glucose control.

Adult↗

PubMed2004

Clinical pharmacokinetics of nateglinide: a rapidly-absorbed, short-acting insulinotropic agent.

The prevalence and medical and economic impact of type 2 diabetes mellitus is increasing in Western societies. New agents have been developed that act primarily to reduce postprandial glucose excursions, which may be of particular significance now that postprandial glucose excursions are known to be correlated with cardiovascular morbidity and mortality. Nateglinide is a phenylalanine derivative that blocks K+ channels in pancreatic beta-cells, facilitating insulin secretion. Nateglinide sensitises beta-cells to ambient glucose, reducing the glucose concentration needed to stimulate insulin secretion. The pharmacokinetics of nateglinide are characterised by rapid absorption and elimination, with good (73%) bioavailability. Nateglinide is more rapidly absorbed when given 0-30 minutes prior to meal ingestion than if given during the meal. Nateglinide is extensively metabolised, primarily by cytochrome P450 2C9, and eliminated primarily by the kidney. Nateglinide pharmacokinetics are linear over the dose range 60-240 mg. No significant pharmacokinetic alterations occur in renally impaired patients, in the elderly, or in mildly hepatically impaired patients. Nateglinide administered prior to meals stimulates rapid, short-lived insulin secretion in a dose-dependent manner, thus decreasing mealtime plasma glucose excursions. Its effects on insulin secretion are synergistic with those of a meal. With increasing nateglinide doses, the risk of hypoglycaemia also increases, but its incidence is low. Even if a meal is missed, and the patient skips the dose of nateglinide (as recommended in the event of a missed meal), the incidence of subsequent hypoglycaemia remains low compared with long-acting agents. The postprandial insulinotropic effects of nateglinide are more rapid than those of repaglinide and more rapid and greater than those of glibenclamide (glyburide), while producing less prolonged insulin exposure and less risk of delayed hypoglycaemia. Further investigation is required to determine if nateglinide inhibition of postprandial glucose excursions will help to prevent diabetic complications or preserve pancreatic beta-cell function.

Area Under Curve↗

PubMed2005

Acute nateglinide administration in subjects with type 2 diabetes: effects on postprandial metabolism, coagulation, and fibrinolysis.

BACKGROUND AND AIM: Postprandial glycaemia and lipaemia are known risk factors for atherosclerosis in type 2 diabetes. Coagulation activation in the postprandial state also contributes to acceleration of atherosclerosis. Nateglinide is effective in reducing postprandial glycaemia. Its effect on glycaemia may also be beneficial in postprandial lipaemia and coagulation. The aim of this study was to examine the potential effect of a single dose of nateglinide on postprandial triglyceridaemia, coagulation, and fibrinolysis in patients with type 2 diabetes. METHODS AND RESULTS: Ten subjects with type 2 diabetes, treated with diet alone were recruited in a crossover randomized study. In the morning, after a 12- to 14-h fast, each subject received a standard mixed meal (total energy 783 kcal), preceded by one tablet of 120 mg nateglinide or placebo. Venous blood samples were drawn prior to meal consumption and 6h afterwards for the measurement of plasma glucose, insulin, and C-peptide, lipids, coagulation, and fibrinolysis factors. As expected, there was a significant reduction in postprandial glycaemia after nateglinide administration compared to placebo (P<0.001). Plasma insulin levels were significantly higher after nateglinide than after placebo (P=0.002). Nateglinide administration resulted in a lower overall postprandial reduction of tissue-plasminogen activator than placebo (-2.9+/-1.3 vs. -8.3+/-3.7 ng/ml h, P=0.003). In addition, a significant reduction of postprandial plasminogen activator inhibitor-1 was observed in comparison with the baseline values after nateglinide (P=0.001), although the overall response was not significantly different after nateglinide and placebo (P=0.31). Plasma concentrations of C-peptide, lipids and the remaining coagulation parameters studied were not different between nateglinide and placebo. CONCLUSIONS: Acute nateglinide administration improves postprandial glycaemia and fibrinolytic activity in patients with type 2 diabetes. This combined effect, if confirmed by a long-treatment study, might reduce cardiovascular risk in type 2 diabetes.

Adult↗

PubMed2002

Comparison of insulinotrophic actions of nateglinide with glibenclamide dissociated from absorption in conscious dogs.

Nateglinide is more rapidly absorbed than glibenclamide. Therefore, the different absorption kinetics of both drugs were eliminated by intraportal administration in conscious fasted dogs. The plasma insulin profiles were compared under similar kinetic changes in plasma drug concentrations. After a priming dose of nateglinide (1 mg/kg. 5 min) or glibenclamide (40 microg/kg. 5 min), plasma drug concentrations reached a peak at 4 minutes (nateglinide, 80 +/- 5 micromol/L, n = 6 and glibenclamide, 263 +/- 60 nmol/L, n = 6) followed by a sustained level at approximately 30% of the peak concentration at 30 minutes. Nateglinide led to a rapid and constant reduction in arterial glucose of approximately 30% basal, while glibenclamide promoted a gradual decrease to approximately 50% basal at 120 minutes. An increase in plasma insulin level by nateglinide of 4 times basal (218 +/- 58 pmol/L v 47 +/- 3 pmol/L, P <.05, n = 6) occurred at 6 to 10 minutes followed by sustained release of 1.4 times basal (67 +/- 15 pmol/L, n = 6). The insulin surge was more than doubled (484 +/- 209 pmol/L, n = 6) under a euglycemic clamp. Insulin release by glibenclamide increased gradually reaching 10-fold basal (449 +/- 166 pmol/L, n = 6) at 60 minutes. This was not enhanced during a euglycemic clamp. Lowering the primed doses of nateglinide resulted in a diminished peak plasma insulin concentration. In contrast, glibenclamide caused only a slower increase, but eventually reaching a similar peak. By increasing the continuous infusion of nateglinide, the sustained insulin release was not altered. Glibenclamide, but not nateglinide, evoked prompt and sustained insulin release in the continuing presence of the other. These results are consistent with the concept that nateglinide produces a quick, but very short-lived, interaction with sulfonylurea (SU)-receptors on plasma membrane by free access of the drug from the cell exterior. In contrast, glibenclamide promotes a slow and longer interaction with the receptor by distribution of the drug into the cell inferior. We conclude, therefore, that not only the different kinetics of gastrointestinal (GI) absorption, but also the inherent difference in the interaction with beta cells is attributed to the different insulin release characteristics between nateglinide and glibenclamide in vivo.

ATP-Binding Cassette Transporters↗

PubMed2004

H+-dependent transport mechanism of nateglinide in the brush-border membrane of the rat intestine.

(-)-N-(trans-4-Isopropylcyclohexanecarbonyl)-D-phenylalanine (nateglinide) is a novel oral hypoglycemic agent possessing a carboxyl group and a peptide-type bond in its structure. Although nateglinide quickly reaches the maximal serum concentration after oral administration, nateglinide itself is not transported by PepT1 or MCT1. The aim of this study was to characterize the transporters on the apical side of the small intestine that are responsible for the rapid absorption of nateglinide. The uptake of nateglinide by rat intestinal brush-border membrane vesicles is associated with a proton-coupled transport system. Ceftibuten competitively inhibited H(+)-dependent nateglinide uptake. Glycylsarcosine (Gly-Sar), cephradine, and cephalexin did not significantly inhibit the uptake of nateglinide. The combination of Gly-Sar and nateglinide greatly reduced the uptake of ceftibuten. The effect of the combined treatment was significantly greater than that of Gly-Sar alone. Furthermore, nateglinide competitively inhibited H(+)-driven ceftibuten transporter-mediated ceftibuten uptake. Ceftibuten transport occurs via at least two H(+)-dependent transport systems: one is PepT1, and the other is the ceftibuten/H(+) cotransport system. On the other hand, we demonstrated that nateglinide transport occurs via a single system that is H(+) dependent but is distinct from PepT1 and may be identical to the ceftibuten/H(+) cotransport system.

Animals↗

PubMed2001

Effects of timing of administration and meal composition on the pharmacokinetic and pharmacodynamic characteristics of the short-acting oral hypoglycemic agent nateglinide in healthy subjects.

These studies examined the influence of timing of administration of nateglinide on the glucose profile and beta-cell secretory response to a standardized test meal and the effect of meal composition on the pharmacokinetic and pharmacodynamic profile. In study 1, nateglinide (60 mg) or placebo was given orally at -10, -1, or +10 min to healthy subjects (n = 12), in relation to a standardized test meal (500 kcal) that commenced at 0 min. In study 2, also in healthy subjects (n = 12), a single oral dose (60 mg) of nateglinide was given either 10 min before or 10 min after the start of each of three different test meals (i.e. high in carbohydrate, fat, or protein). In both studies, the postmeal observation period was a minimum of 240 min. In the first study premeal (-10,-1 min), administration of nateglinide led to earlier and higher peak plasma nateglinide concentrations, compared with postprandial dosing (+10 min). A significantly lower maximum postprandial glucose concentration was seen with preprandial dosing compared with either placebo (P < 0.01) or nateglinide given postprandially (P < 0.01). The impact on the glucose profile was consistent with the enhanced insulin profiles after nateglinide, resulting in higher peak plasma insulin concentrations compared with placebo (P < 0.01). Study 2 confirmed the greater impact of pre- vs. postprandial dosing on the glucose and insulin profiles, irrespective of meal type. Nateglinide administration, before a meal, resulted in a more rapid rise and higher peak nateglinide plasma concentrations, irrespective of meal composition. Preprandial administration of nateglinide was more effective in reducing prandial glucose excursions, compared with postmeal dosing (+10 min), a consequence of the earlier insulin response.

Area Under Curve↗

PubMed2004

Influence of CYP2C9 and CYP2D6 polymorphisms on the pharmacokinetics of nateglinide in genotyped healthy volunteers.

BACKGROUND: The oral hypoglycaemic drug nateglinide is eliminated from the human body via hepatic biotransformation and renal tubular secretion. According to in vitro data, about 70% of nateglinide intrinsic clearance may be mediated by cytochrome P450 (CYP) 2C9 and a smaller fraction by CYP3A4 and CYP2D6. OBJECTIVE: To assess the impact of CYP2C9 polymorphisms and of the CYP2D6 poor metaboliser genotype on the pharmacokinetics of nateglinide and its effects on insulin, glucose and glucagon in plasma. DESIGN AND PARTICIPANTS: A prospective clinical study in 26 healthy volunteers chosen for their CYP2C9 and CYP2D6 genotype was conducted with individuals carrying wild-type genotype as reference group. METHODS: Serial plasma nateglinide, glucose, insulin and glucagon concentrations were measured over 34 hours after a 180 mg dose of nateglinide under challenge with 75 g of oral glucose at 0, 4 and 8 hours after nateglinide intake. Kinetics were evaluated by nonparametric methods and by population pharmacokinetic-pharmacodynamic modelling. RESULTS: Significantly reduced oral nateglinide clearance was found in carriers of CYP2C9*3 alleles, (p < 0.01), whereas carriers of CYP2C9*2 alleles had kinetic parameters similar to those of carriers of the wild-type allele (p = nonsignificant). Median total clearances were 7.9, 8.4, 6.5, 6.9, 5.8 and 4.1 L/h in carriers of the CYP2C9 genotypes *1/*1, *1/*2, *2/*2, *1/*3, *2/*3 and *3/*3. Median clearance in three carriers of two deficient CYP2D6 alleles was 9.4 L/h. These differences in nateglinide kinetics due to CYP2C9 genotypes did not result in statistically significant differences in plasma glucose, insulin and glucagon. Pharmacokinetic-pharmacodynamic modelling revealed a minor effect of CYP2C9 genotype on insulin and glucose, and extrapolations indicated that carriers of the CYP2C9*3/*3 genotype may be at a slightly higher risk of hypoglycaemia compared with carriers of CYP2C9*1, particularly when taking nateglinide doses above 120 mg. CONCLUSION: The effect of CYP2C9 polymorphisms on nateglinide kinetics may cause a slightly increased risk for hypoglycaemia, which may become relevant in diabetic patients.

Adult↗