Chemical formula: C₁₉H₂₇NO₃ Molecular mass: 317.429 g/mol PubChem compound: 5311309
Nateglinide is an amino acid (phenylalanine) derivative, which is chemically and pharmacologically distinct from other antidiabetic agents. Nateglinide is a rapid, short-acting oral insulin secretagogue. Its effect is dependent on functioning beta cells in the pancreas islets.
Early insulin secretion is a mechanism for the maintenance of normal glycaemic control. Nateglinide, when taken before a meal, restores early or first phase insulin secretion, which is lost in patients with type 2 diabetes, resulting in a reduction in post-meal glucose and HbA1c.
Nateglinide closes ATP-dependent potassium channels in the beta-cell membrane with characteristics that distinguish it from other sulphonylurea receptor ligands. This depolarises the beta cell and leads to an opening of the calcium channels. The resulting calcium influx enhances insulin secretion.
Electrophysiological studies demonstrate that nateglinide has 45-300-fold selectivity for pancreatic beta cell versus cardiovascular K+ATP channels.
In type 2 diabetic patients, the insulinotropic response to a meal occurs within the first 15 minutes following an oral dose of nateglinide. This results in a blood-glucose-lowering effect throughout the meal period. Insulin levels return to baseline within 3 to 4 hours, reducing post-meal hyperinsulinaemia.
Nateglinide-induced insulin secretion by pancreatic beta cells is glucose-sensitive, such that less insulin is secreted as glucose levels fall. Conversely, the coadministration of food or a glucose infusion results in an enhancement of insulin secretion.
In combination with metformin, which mainly affected fasting plasma glucose, the effect of nateglinide on HbA1c was additive compared to either agent alone.
Nateglinide is rapidly absorbed following oral administration of nateglinide tablets prior to a meal, with mean peak drug concentration generally occurring in less than 1 hour. Nateglinide is rapidly and almost completely (≥90%) absorbed from an oral solution. Absolute oral bioavailability is estimated to be 72%.
The steady-state volume of distribution of nateglinide based on intravenous data is estimated to be approximately 10 litres. In vitro studies show that nateglinide is extensively bound (97-99%) to serum proteins, mainly serum albumin and to a lesser extent alphai-acid glycoprotein. The extent of serum protein binding is independent of drug concentration over the test range of 0.1-10 μg nateglinide/ml.
Nateglinide is extensively metabolised. The main metabolites found in humans result from hydroxylation of the isopropyl side-chain, either on the methine carbon, or one of the methyl groups; activity of the main metabolites is about 5-6 and 3 times less potent than nateglinide, respectively. Minor metabolites identified were a diol, an isopropene and acyl glucuronide(s) of nateglinide; only the isopropene minor metabolite possesses activity, which is almost as potent as nateglinide. Data available from both in vitro and in vivo experiments indicate that nateglinide is predominantly metabolised by CYP2C9 with involvement of CYP3A4 to a smaller extent.
Nateglinide and its metabolites are rapidly and completely eliminated. Most of the [14C] nateglinide is excreted in the urine (83%), with an additional 10% eliminated in the faeces. Approximately 75% of the administered [14C] nateglinide is recovered in the urine within six hours post-dose. Approximately 6-16% of the administered dose was excreted in the urine as unchanged drug. Plasma concentrations decline rapidly and the elimination half-life of nateglinide typically averaged 1.5 hours in all studies of nateglinide in volunteers and type 2 diabetic patients. Consistent with its short elimination half-life, there is no apparent accumulation of nateglinide upon multiple dosing with up to 240 mg three times daily.
In patients with type 2 diabetes who were given nateglinide with a dose range of 60 mg to 240 mg before meals three times a day for one week, nateglinide showed linear pharmacokinetics for both AUC and Cmax. Tmax was independent of dose.
Age did not influence the pharmacokinetic properties of nateglinide.
The systemic availability and half-life of nateglinide in non-diabetic subjects with mild to moderate hepatic impairment did not differ to a clinically significant degree from those in healthy subjects.
The systemic availability and half-life of nateglinide in diabetic patients with mild, moderate (creatinine clearance 31-50 ml/min) and severe (creatinine clearance 15-30 ml/min) renal impairment (not undergoing dialysis) did not differ to a clinically significant degree from those in healthy subjects. There is a 49% decrease in Cmax of nateglinide in dialysis-dependent diabetic patients. The systemic availability and half-life in dialysis-dependent diabetic patients was comparable with healthy subjects. Although safety was not compromised in this population dose adjustment may be required in view of low Cmax.
Repeated dosing with 90 mg once daily for 1 to 3 months in diabetic patients with end-stage renal disease (ESRD) showed pronounced M1 metabolite accumulation up to 1.2 ng/ml despite the reduced dose. M1 concentration decreased markedly after haemodialysis. Although M1 metabolites show only slight hypoglycaemic activity (approximately 5 times lower than nateglinide), metabolite accumulation might increase the hypoglycaemic effect of the administered dose. Therefore, dose discontinuation is advisable in patients with severe renal impairment who present with potentiation of hypoglycaemic effect while on nateglinide.
No clinically significant differences in nateglinide pharmacokinetics were observed between men and women.
When given post-prandially, the extent of nateglinide absorption (AUC) remains unaffected. However, there is a delay in the rate of absorption characterised by a decrease in Cmax and a delay in time to peak plasma concentration (tmax). It is recommended that nateglinide be administered prior to meals. It is usually taken immediately (1 minute) before a meal but may be taken up to 30 minutes before meals.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to fertility and post-natal development. Nateglinide was not teratogenic in rats. In rabbits, embryonic development was adversely affected and the incidence of gallbladder agenesis or small gallbladder was increased at doses of 300 and 500 mg/kg (approximately 24 and 28 times the human therapeutic exposure with a maximum recommended nateglinide dose of 180 mg, three times daily before meals), but not at 150 mg/kg (approximately 17 times the human therapeutic exposure with a maximum recommended nateglinide dose of 180 mg, three times daily before meals).
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