Volume 36, Issue 11 p. 1012-1021

Pharmacokinetics and Pharmacodynamics of Metformin in Healthy Subjects and Patients with Noninsulin-Dependent Diabetes Mellitus

Dr. Nancy C. Sambol PharmD

Corresponding Author

Dr. Nancy C. Sambol PharmD

Department of Biopharmaceutical Sciences, University of California San Francisco, San Francisco, California

Department of Clinical Pharmacy, University of California San Francisco, San Francisco, California

Department of Biopharmaceutical Sciences, University of California San Francisco, San Francisco, CA 94143–0446.Search for more papers by this author
Dr. Janie Chiang PhD

Dr. Janie Chiang PhD

Department of Biopharmaceutical Sciences, University of California San Francisco, San Francisco, California

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Dr. Michael O'Conner MD

Dr. Michael O'Conner MD

Department of Medicine, University of California San Francisco, San Francisco, California

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Dr. Chui Y. Liu PhD

Dr. Chui Y. Liu PhD

Department of Biopharmaceutical Sciences, University of California San Francisco, San Francisco, California

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Dr. Emil T. Lin PhD

Dr. Emil T. Lin PhD

Department of Biopharmaceutical Sciences, University of California San Francisco, San Francisco, California

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Dr. Anita M. Goodman MD

Dr. Anita M. Goodman MD

Lipha Pharmaceuticals, Inc., New York, New York.

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Dr. Leslie Z. Benet PhD

Dr. Leslie Z. Benet PhD

Department of Biopharmaceutical Sciences, University of California San Francisco, San Francisco, California

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Dr. John H. Karam MD

Dr. John H. Karam MD

Department of Medicine, University of California San Francisco, San Francisco, California

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First published: November 1996
Citations: 125

Abstract

This study was conducted to assess the effect of noninsulin-dependent diabetes mellitus (NIDDM) and gender on the pharmacokinetics of metformin and to investigate whether or not metformin exhibits dose-dependent pharmacokinetics. The pharmacodynamic effects (on plasma glucose and insulin) of metformin in patients with NIDDM and in healthy subjects also were assessed. Nine patients with NIDDM and 9 healthy subjects received 4 single-blind single-dose treatments of metformin HCl (850 mg, 1,700 mg, 2,550 mg, and placebo) and a multiple-dose treatment of 850 mg metformin HCl (3 times daily for 19 doses). After each single-dose treatment and the final dose of the multiple-dose phase, multiple plasma and urine samples were collected for 48 hours and assayed for metformin levels. Plasma samples were also assayed for glucose and insulin levels. There were no significant differences in metformin kinetics in patients with NIDDM compared with healthy subjects, in men compared with women, or during multiple-dose treatment versus single-dose treatment. Plasma concentrations of metformin increase less than proportionally to dose, most likely due to a decrease in percent absorbed. In patients with NIDDM, single doses of 1,700-mg or higher of metformin significantly decrease postprandial, but not preprandial, glucose concentrations and do not influence insulin concentrations. With multiple doses, both preprandial and postprandial glucose concentrations and preprandial insulin concentrations were significantly lower than with placebo. The effect of metformin on glucose level is correlated with the average fasting plasma glucose level without drug. In healthy subjects, single and multiple doses of metformin showed no effect on plasma glucose, but significantly attenuated the rise in immediate postprandial insulin levels.