Nateglinide

(USAN, rINN)
Nateglinide Chemical formula
Synonyms: A-4166; AY-4166; DJN-608; Nateglinid; Nateglinida; Natéglinide; Nateglinidi; Nateglinidum; SDZ-DJN-608; Senaglinide; YM-026. (−)N-[(trans-4-Isopropylcyclohexyl)carbonyl]
Cyrillic synonym: Натеглинид.

💊 Chemical information

Chemical formula: C19H27NO3 = 317.4.
CAS — 105816-04-4.
ATC — A10BX03.
ATC Vet — QA10BX03.

💊 Adverse Effects and Precautions

As for Repaglinide.

Overdosage.

A blood-glucose concentration of 2.0 mmol/litre was measured 1 hour after ingestion of nateglinide 3.42 g in a 30year-old woman.1 She was able to walk unaided, but seemed drowsy. The hypoglycaemic effect of nateglinide lasted for 6 hours and was treated with intravenous glucose (total dose 100 g).
1. Nakayama S, et al. Hypoglycemia following a nateglinide overdose in a suicide attempt. Diabetes Care 2005; 28: 227–8.

Renal impairment.

A single-dose pharmacokinetic study1found that moderate to severe renal impairment (creatinine clearance 15 to 50 mL/minute per 1.73 m2) and haemodialysis did not significantly affect the pharmacokinetics of nateglinide. However, the metabolite M1 has been found to accumulate in patients with renal impairment requiring haemodialysis after repeated doses of nateglinide, but it may be removed by haemodialysis.2M1 is a major metabolite that has modest hypoglycaemic activity compared with nateglinide. An analysis3 of pooled study data found that efficacy and tolerability of nateglinide in elderly diabetic patients were not significantly affected by renal impairment (mean creatinine clearance 50.9 mL/minute per 1.73 m2). Nevertheless, a 56-year-old diabetic woman whose renal failure was managed with haemodialysis experienced severe hypoglycaemia with nateglinide; the reaction was attributed to the accumulation of M1.4 Licensed product information in the UK and USA suggest that no dosage adjustment is necessary in renal impairment, although UK information suggests that dose adjustment might be required in patients on haemodialysis.
1. Devineni D, et al. Pharmacokinetics of nateglinide in renally impaired diabetic patients. J Clin Pharmacol 2003; 43: 163–70
2. Inoue T, et al. Pharmacokinetics of nateglinide and its metabolites in subjects with type 2 diabetes mellitus and renal failure. Clin Nephrol 2003; 60: 90–5
3. Del Prato S, et al. Treatment of patients over 64 years of age with type 2 diabetes: experience from nateglinide pooled database retrospective analysis. Diabetes Care 2003; 26: 2075–80
4. Nagai T, et al. Hypoglycemia due to nateglinide administration in diabetic patient with chronic renal failure. Diabetes Res Clin Pract 2003; 59: 191–4.

💊 Interactions

As with other oral antidiabetics, the efficacy of nateglinide may be affected by drugs independently increasing or decreasing blood glucose concentrations.
1. Scheen AJ. Drug-drug and food-drug pharmacokinetic interactions with new insulinotropic agents repaglinide and nateglinide. Clin Pharmacokinet 2007; 46: 93–108.

Antibacterials.

In a study1 of healthy subjects, rifampicin reduced the plasma concentrations and half-life of nateglinide, probably by induction of its metabolism by the cytochrome P450 isoenzyme CYP2C9. The glucose-lowering effect of nateglinide was not affected, but there was a marked interindividual variation in the pharmacokinetic changes, and the authors suggested that some diabetic patients could be affected.
1. Niemi M, et al. Effect of rifampicin on the pharmacokinetics and pharmacodynamics of nateglinide in healthy subjects. Br J Clin Pharmacol 2003; 56: 427–32.

Antifungals.

In a study1 of healthy subjects, fluconazole raised the plasma concentrations and prolonged the half-life of nateglinide, probably by inhibition of its metabolism by the cytochrome P450 isoenzyme CYP2C9. The glucose-lowering effect of nateglinide was not affected, but a low dose of nateglinide had been used and the authors suggested that in diabetic patients fluconazole may enhance and prolong the effects of nateglinide.
1. Niemi M, et al. Effect of fluconazole on the pharmacokinetics and pharmacodynamics of nateglinide. Clin Pharmacol Ther 2003; 74: 25–31.

Lipid regulating drugs.

A study1 investigating the effects of the gemfibrozil and itraconazole combination on the pharmacokinetics of nateglinide showed only a limited interaction. Nateglinide plasma concentrations were raised moderately and the blood glucose response to nateglinide was not significantly changed. This is in contrast to the substantial interaction of gemfibrozil with repaglinide.
1. Niemi M, et al. Coadministration of gemfibrozil and itraconazole has only a minor effect on the pharmacokinetics of the CYP2C9 and CYP3A4 substrate nateglinide. Br J Clin Pharmacol 2005; 60: 208–17.

💊 Pharmacokinetics

Nateglinide is rapidly absorbed after oral doses, with peak plasma concentrations occurring within one hour and an absolute bioavailability of 73%. Nateglinide is 98% bound to plasma proteins. It is mainly metabolised by cytochrome P450 isoenzyme CYP2C9, and to a lesser extent by CYP3A4. Major metabolites include M1 which is less potent than nateglinide. The parent drug and metabolites are mainly excreted in the urine but about 10% is eliminated in the faeces. The elimination half-life is about 1.5 hours.
1. Choudhury S, et al. Single-dose pharmacokinetics of nateglinide in subjects with hepatic cirrhosis. J Clin Pharmacol 2000; 40: 634–40
2. Devineni D, et al. Pharmacokinetics of nateglinide in renally impaired diabetic patients. J Clin Pharmacol 2003; 43: 163–70
3. McLeod JF. Clinical pharmacokinetics of nateglinide: a rapidlyabsorbed, short-acting insulinotropic agent. Clin Pharmacokinet 2004; 43: 97–120.

💊 Uses and Administration

Nateglinide, like repaglinide, is a meglitinide antidiabetic used in the treatment of type 2 diabetes mellitus. It is given within the 30 minutes before meals in oral doses of 60 or 120 mg three times daily. This may be increased to 180 mg three times daily if necessary. Nateglinide is also given in similar doses with metformin or a thiazolidinedione in type 2 diabetes not adequately controlled by these drugs alone. Although dose adjustment is not generally required in renal impairment, hypoglycaemia has been attributed to accumulation of the metabolite M1 (see above).
1. Dunn CJ, Faulds D. Nateglinide. Drugs 2000; 60: 607–15
2. Hanefeld M, et al. Rapid and short-acting mealtime insulin secretion with nateglinide controls both prandial and mean glycemia. Diabetes Care 2000; 23: 202–7
3. Horton ES, et al. Nateglinide alone and in combination with metformin improves glycemic control by reducing mealtime glucose levels in type 2 diabetes. Diabetes Care 2000; 23: 1660–5.
4. Levien TL, et al. Nateglinide therapy for type 2 diabetes mellitus. Ann Pharmacother 2001; 35: 1426–34
5. Fonseca V. et al. Addition of nateglinide to rosiglitazone monotherapy suppresses mealtime hyperglycemia and improves overall glycemic control. Diabetes Care 2003; 26: 1685–90
6. Campbell IW. Nateglinide—current and future role in the treatment of patients with type 2 diabetes mellitus. Int J Clin Pract 2005; 59: 1218–28.

💊 Preparations

Proprietary Preparations

Arg.: Nateglin; Starlix; Braz.: Starlix; Canad.: Starlix; Chile: Gluconol; Starlix; Cz.: Starlix; Trazec; Denm.: Starlix†; Fin.: Starlix; Ger.: Starlix; Gr.: Starlix; Hong Kong: Starlix†; Hung.: Starlix; India: Glinate; Indon.: Starlix; Irl.: Starlix; Jpn: Starsis; Malaysia: Starlix; Mex.: Starlix; Neth.: Starlix; Trazec; Norw.: Starlix; NZ: Starlix†; Philipp.: Starlix; Port.: Starlix; Trazec; Rus.: Starlix (Старликс); S.Afr.: Starlix; Singapore: Starlix; Spain: Starlix; Swed.: Starlix; Switz.: Starlix; Turk.: Starlix; UK: Starlix; USA: Starlix; Venez.: Starlix. Multi-ingredient: Braz.: Starform; Venez.: Starform.
Published November 17, 2018.