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Potential Pharmacokinetics Interference Between -Glucosidase Inhibitors and Other Oral Antidiabetic Agents

Division of Diabetes, Nutrition and Metabolic Disorders and the Division of Clinical Pharmacology and Therapeutics, Department of Medicine, CHU Sart Tilman, Liège, Belgium

In the study recently reported by Chiasson et al. (1), it was concluded that miglitol, a pseudomonosaccharide -glucosidase inhibitor, can be combined effectively with metformin therapy to give significantly greater reductions in HbA_1c and postprandial plasma glucose levels than metformin alone in middle-aged patients in whom type 2 diabetes is insufficiently controlled by diet alone. The combined therapy had a good safety profile, with only a trend toward an increase in the number of gastrointestinal side-effects due to miglitol acting at the small intestine by delaying the digestion of complex carbohydrates (2).

The absorption of metformin occurs mainly in the small intestine, and it has been shown that high concentrations of the compound (10–100 times plasma levels) accumulate in the walls of the gastrointestinal tract (rev. in 3). Therefore, possible pharmacokinetic interference with drugs acting on the intestinal wall are not excluded. We previously demonstrated in six healthy subjects that acarbose (100 mg), a pseudotetrasaccharide that is currently the leading -glucosidase inhibitor on the market, induces significant reductions in early (90-, 120-, and 180-min) serum levels, peak concentrations (C_max 1.22 ± 0.14 vs. 1.87 ± 0.60 mg/l; P < 0.05), and area under the curve for 0–540 min (AUC_{0–540 min}; 423 ± 55 vs. 652 ± 55 mg · min · l^-1; P < 0.05) of metformin ingested as two tablets of 500 mg with a standardized breakfast (4).

To our knowledge, such interference of miglitol on the pharmacokinetics of metformin has not yet been studied. However, although our group did not observe any significant alteration of the glibenclamide pharmacokinetics in acarbose-treated type 2 diabetic patients (5), we observed slight modifications of the pharmacokinetic parameters of glibenclamide after ingestion of miglitol in six healthy volunteers (unpublished data). In a double-blind crossover trial, each subject was randomly allocated during two consecutive 7-day periods to either miglitol (3 x 50 mg during the first 3 days and 3 x 100 mg/day during the last 4 days) or placebo. At the 7th and 14th day of the study, the overnight-fasted subjects ingested 5 mg glibenclamide with the first bite of a standardized breakfast together with either 100 mg miglitol or placebo. Venous blood samples were taken from 0 to 540 min to measure serum glibenclamide concentrations by radioimmunoassay. Time-to-peak (T_max; 215 ± 40 vs. 230 ± 24 min; NS) and peak serum glibenclamide levels (C_max; 190 ± 33 vs. 225 ± 31 µg/l; NS) were similar after miglitol and placebo, respectively. However, the glibenclamide AUC_{0–540 min} was significantly lower after miglitol than after placebo (40,358 ± 3,203 vs. 59,950 ± 9,193 µg · min · l^-1; P < 0.05).

These observations in normal subjects suggest that a potential interference of miglitol on the pharmacokinetics of metformin cannot be excluded during combined therapy in type 2 diabetic patients. Whether this interference exists and to what extent it may influence the efficacy and/or safety of such a combined therapy remains to be investigated.

Footnotes

Address correspondence to Dr. André J. Scheen, Department of Medicine, Centre Hospitalier Universitaire Sart Tilman, B-4000 Liège, Belgium. E-mail: andre.scheen{at}chu.ulg.ac.be.

References

1. Chiasson J-L, Naditch L, for the Miglitol Canadian University Investigator Group: The synergistic effect of miglitol plus metformin combination therapy in the treatment of type 2 diabetes. Diabetes Care 24:989–994, 2001[Abstract/Free Full Text]
   
2. Scott LJ, Spencer CM: Miglitol: a review of its therapeutic potential in type 2 diabetes mellitus. Drugs 59:521–549, 2000[Medline]
   
3. Scheen AJ: Clinical pharmacokinetics of metformin. Clin Pharmacokin 30:359–371, 1996[Medline]
   
4. Scheen AJ, Ferreira Alves de Magalhaes C, Salvatore T, Lefèbvre PJ: Reduction of the acute bioavailability of metformin by the alpha-glucosidase inhibitor acarbose in normal man. Eur J Clin Invest 24(Suppl. 3):50–54, 1994
   
5. Gérard J, Lefèbvre PJ, Luyckx AS: Glibenclamide pharmacokinetics in acarbose-treated type 2 diabetics. Eur J Clin Pharmacol 27:233–236, 1984 [Medline]
   

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This Article Extract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Scheen, A. J. Articles by Lefèbvre, P. J. Search for Related Content PubMed PubMed Citation Articles by Scheen, A. J. Articles by Lefèbvre, P. J. Social Bookmarking                What's this?