Disease relevance of nateglinide

• In chronic renal failure, the oral agents that can be used therefore include the insulin secretagogues repaglinide and nateglinide and the thiazolidinediones (rosiglitazone and pioglitazone) with caution [1].
• CONCLUSIONS: Nateglinide was safe and effective in reducing postprandial hyperglycemia in subjects with IGT [2].
• Synergistic effects of nateglinide and meal administration on insulin secretion in patients with type 2 diabetes mellitus [3].
• Hypoglycemia following a nateglinide overdose in a suicide attempt [4].
• 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 [5].

High impact information on nateglinide

• Mutation of serine 1237 in SUR1 to tyrosine (S1237Y) abolished tolbutamide and nateglinide block, suggesting that these drugs share a common point of interaction on the SUR1 subunit of the ATP-sensitive K(+) channel [6].
• RESULTS: Although oral administration of nateglinide and repaglinide elicited similar maximum increments of plasma insulin (+403 and +448 pmol/l, respectively), the effects of nateglinide were more rapidly manifest and less prolonged [7].
• METHODS: First, equipotent doses of nateglinide (20 mg/kg) and repaglinide (0.1 mg/kg) or vehicle were given intragastrically to overnight-fasted ketamine-anesthetized pre-diabetic Cynomolgus monkeys and samples were obtained for measurement of plasma glucose, insulin, glucagon, NEFA and drug concentrations [7].
• RESULTS: Insulin peaked earlier after nateglinide than after glibenclamide or placebo (median [interquartile range] time 70 [50] vs. 110 [20] vs. 110 [30] min, P = 0.0002 and P = 0.0025, respectively) [8].
• RESEARCH DESIGN AND METHODS: Mild type 2 diabetic men and women (n = 108; fasting glucose 7.0-8.3 mmol/l) on diet treatment alone randomly received 30, 60, or 120 mg nateglinide or placebo for 24 weeks [9].

Chemical compound and disease context of nateglinide

• CONCLUSIONS: A single dose of nateglinide administered to diet-treated type 2 diabetic patients with fasting hyperglycemia increased insulin secretion and reduced fasting glucose without hypoglycemia [10].
• In subgroups in which metformin and long-acting sulfonylureas must be used with caution, nateglinide had a low risk of adverse events and hypoglycemia [11].
• The clinical decision to use glipizide versus nateglinide should be based on factors other than the control of postprandial hyperglycemia in type 2 diabetes [12].
• Addition of nateglinide to rosiglitazone monotherapy suppresses mealtime hyperglycemia and improves overall glycemic control [13].
• Therefore, a DPP-IV inhibitor in combination with glybenclamide or nateglinide may be a promising option for the treatment of type 2 diabetes, and particularly, for controlling postprandial hyperglycemia in the clinic [14].

Biological context of nateglinide

• Effect of fluconazole on the pharmacokinetics and pharmacodynamics of nateglinide [15].
• Rosiglitazone ameliorated insulin resistance by 60% compared with nateglinide [16].
• During the solid meal challenges, nateglinide and glyburide elicited similar overall glucose control ( 12-h incremental AUC = -13.2 vs. -15.3 mmol. h/l), but the insulin AUC induced by nateglinide was significantly less than that induced by glyburide ( 12-h AUC = +866 vs. +1,702 pmol. h/l, P = 0.01) [17].
• At low concentration (10 microm), nateglinide did not induce beta-cell apoptosis [18].
• The pharmacokinetics of nateglinide are characterised by rapid absorption and elimination, with good (73%) bioavailability [19].

Anatomical context of nateglinide

• In the present study, we investigated the effect of A-4166 on the cytosolic free Ca2+ concentration ([Ca2+]i) in pancreatic beta-cells from normal rats by dual wavelength fura-2 microfluorometry [20].
• Transport and uptake of nateglinide in Caco-2 cells and its inhibitory effect on human monocarboxylate transporter MCT1 [21].
• H+-dependent transport mechanism of nateglinide in the brush-border membrane of the rat intestine [22].
• 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 [22].
• We also examined whether nateglinide is transported via monocarboxylate transport-1 (MCT1) by means of an uptake study using MCT1-expressing Xenopus laevis oocytes [21].

Associations of nateglinide with other chemical compounds

• Plasma glucose, radioimmunoassay insulin, and nateglinide were measured at baseline and for a further 180 min [10].
• RESEARCH DESIGN AND METHODS--This randomized, double-blind, placebo-controlled multicenter study was conducted in 152 patients who received either nateglinide (120 mg before three meals daily, n = 51), glyburide (5 mg q.d. titrated to 10 mg q.d. after 2 weeks, n = 50), or placebo (n = 51) for 8 weeks [17].
• RESEARCH DESIGN AND METHODS: In this randomized double-blind study, patients with an HbA1c level between 6.8 and 11.0% during a 4-week placebo run-in received 24 weeks' treatment with 120 mg nateglinide before meals (n = 179), 500 mg metformin three times a day (n = 178), combination therapy (n = 172), or placebo (n = 172) [23].
• The area under the curve for the glucose excursion above baseline was also higher with placebo (14.1 +/- 1.8 mmol/h. l) compared with glipizide (6.9 +/- 2.4 mmol/h. l, P = 0.002), nateglinide (9.7 +/- 2 mmol/h. l, P = 0.004), or glipizide plus nateglinide (5.6 +/- 2.2 mmol/h. l, P < 0.001) [12].
• The peak plasma concentration of the M7 metabolite of nateglinide was reduced by 34% by fluconazole (P <.001), and its half-life was prolonged from 2.2 to 3.5 hours (P <.05) [15].

Gene context of nateglinide

• CONCLUSION: The effect of CYP2C9 polymorphisms on nateglinide kinetics may cause a slightly increased risk for hypoglycaemia, which may become relevant in diabetic patients [24].
• 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 [24].
• Our aim was to investigate the effects of the gemfibrozil-itraconazole combination on the pharmacokinetics and pharmacodynamics of another meglitinide analogue, nateglinide, which is metabolized by CYP2C9 and CYP3A4 [25].
• MgADP or MgUDP (100 microM) augmented the inhibitory effect of nateglinide on SUR1/Kir6.2 but not SUR1(S1237Y)/Kir6.2 or SUR2A/Kir6.2 channels [26].
• Inhibitory effect of novel oral hypoglycemic agent nateglinide (AY4166) on peptide transporters PEPT1 and PEPT2 [27].

Analytical, diagnostic and therapeutic context of nateglinide

• Repaglinide versus nateglinide monotherapy: a randomized, multicenter study [5].
• Mild hypoglycaemia was the most frequently reported adverse event (1.3% of patients) after treatment with nateglinide 120 mg 3 times daily in a 16-week clinical study [28].
• METHODS: A double-blind, placebo-controlled trial, examining the effects of a single oral dose of 60 mg nateglinide, given 20 min prior to an intravenous glucose tolerance test (IGTT), on insulin secretion in 10 otherwise healthy Caucasian men with recently diagnosed Type 2 diabetes (duration since diagnosis 0-44 months) [29].
• 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 [30].
• Serial plasma samples were collected for 24 h postdose and analyzed for SDZ DJN 608 using HPLC [31].

References