Vol. 29, Issue 4, 415-421, April 2001

Pharmacokinetics and Metabolism of Nateglinide in Humans

Margaret L. Weaver, Barbara A. Orwig, Lolita C. Rodriguez, Elizabeth D. Graham, Jefferson A. Chin, Michael J. Shapiro, James F. McLeod, and James B. Mangold

Drug Metabolism and Pharmacokinetics, Preclinical Safety (M.L.W., B.A.O., L.C.R., E.D.G., J.B.M.), Clinical Pharmacology, and Clinical Research (J.F.M.), Novartis Institute for Biomedical Research, East Hanover, New Jersey; and Core Technologies (J.A.C., M.J.S.), Novartis Institute for Biomedical Research, Summit, New Jersey

The pharmacokinetics and metabolism of nateglinide were studied in six healthy male subjects receiving a single oral (120 mg) and intravenous (60 mg) dose of [¹⁴C]nateglinide in randomized order. Serial blood and complete urine and feces were collected for 120 h post dose. Nateglinide was rapidly (~90%) absorbed, with peak blood and plasma concentrations at ~1 h post dose. The maximal plasma concentrations of radioactivity (6360 ngEq/ml) and nateglinide (5690 ng/ml) were comparable, and plasma radioactivity concentrations were about twice those of blood at all times. Oral bioavailability was 72%, indicating only a modest first-pass effect. After either dose, plasma nateglinide concentrations declined rapidly with elimination half-lives of 1.5 to 1.7 h and plasma clearance of 7.4 l/h. Plasma radioactivity was eliminated more slowly with half-lives of 52 and 35 h in plasma and blood, respectively, after the oral dose. The contribution of this more slowly eliminated component to the AUC_0- was minor. Nateglinide was extensively metabolized, with excretion predominantly (84-87%) in urine. Only ~16% of the dose was excreted unchanged in urine after either dosing route. The major metabolites were the result of oxidative modifications of the isopropyl group. Three of these were monohydroxylated, two of which appeared to be diastereoisomers. Additionally, one metabolite with an unsaturation in the isopropyl group and two diol-containing isomers were identified. Glucuronic acid conjugates resulting from direct glucuronidation of the carboxylic acid were also present. The major metabolite in plasma and urine was the result of hydroxylation of the methine carbon of the isopropyl group.