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Clinical Pharmacokinetics of Nateglinide

A Rapidly-Absorbed, Short-Acting Insulinotropic Agent

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Abstract

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 β-cells, facilitating insulin secretion. Nateglinide sensitises β-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 60–240mg. 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 β-cell function.

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Acknowledgements

Sincerest thanks are extended to Cynthia Lategan, Pratapa Prasad and Monica Ligueros-Saylan for their contributions to the preparation and review of the manuscript. The author has provided no information on sources of funding or on conflicts of interest directly relevant to the content of this review.

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  1. Novartis Pharmaceuticals, One Health Plaza, East Hanover, New Jersey, 07936, USA

    James F. McLeod

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McLeod, J.F. Clinical Pharmacokinetics of Nateglinide. Clin Pharmacokinet 43, 97–120 (2004). https://doi.org/10.2165/00003088-200443020-00003

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