Issue 167 Item 11 Fluconazole Increases Plasma Concentrations of Nateglinide

Clinicians should be aware of the possibility of increased blood glucose-lowering efficacy of nateglinide if fluconazole and nateglinide are combined.

Fluconazole potently inhibits cytochrome P450 (CYP) 2C9, the authors explain, and in vitro studies suggest that CYP2C9, as well as CYP3A4, participates in the biotransformation of nateglinide.
Dr. Niemi and colleagues from University of Helsinki, Finland, studied the single-dose pharmacokinetics of nateglinide with or without fluconazole administration (400 mg on day 1 and 200 mg on days 2-4) in 10 healthy volunteers.

Fluconazole increased the area under the time-concentration curve (AUC) of nateglinide by 48% and prolonged its half-life from 1.6 to 1.9 hours, the authors report.

The maximum concentration of nateglinide’s principal metabolite fell by 34%, the report indicates, but the metabolite’s half-life increased from 2.2 to 3.5 hours. Nateglinide’s maximum plasma concentration did not change significantly.

Blood glucose levels were not significantly different with and without the administration of fluconazole, the researchers note.
In previous studies, the same fluconazole treatment resulted in a 138% increase in the AUC of the sulfonylurea glimepiride, the investigators write, and a 100-mg daily dose of fluconazole significantly increased the AUC of glipizide (49%) and glyburide (44%).

Dr. Niemi commented that, "It is possible (I would not yet say probable, because of lack of data from patients with type 2 diabetes mellitus) that nateglinide is a safer hypoglycemic drug than glimepiride (and possibly other sulfonylureas) if fluconazole therapy is required." Clin Pharmacol Ther 2003;74:25-31.

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Did YOU KNOW:
Metformin Reduces Inflammation: Common diabetes drug lowers risk by inhibiting proinflammatory factor. University at Buffalo (UB) endocrinologists have shown for the first time that the concentration of a proinflammatory compound known as MIF is increased in the blood plasma of the obese, and that metformin, a standard medicine prescribed for diabetes, suppresses its formation. Presented at the 85th annual meeting of the Endocrine Society held recently in Philadelphia and at the preceding American Diabetes Association meeting in New Orleans.