Rapid and simple high-performance liquid chromatographic assay for the determination of metformin in human plasma and breast milk

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Metformin, unlike the other major antihyperglycaemic drugs, is not associated with weight gain.• Ghrelin is an appetite-stimulating hormone whose concentrations vary in relation to food, obesity and diabetes control.• Reports are conflicting about how metformin affects ghrelin concentrations, and this study was aimed at resolving this issue in patients with Type 2 diabetes. WHAT THIS STUDY ADDS• In this study an increase in ghrelin concentrations was seen in response to metformin treatment in patients with Type 2 diabetes. • This effect was opposite to what might be expected if the effect of metformin on weight control was mediated via suppression of ghrelin.• It is likely that the ghrelin response was secondary to improved glycaemic control.• Meal time changes in appetite and satiety did not correlate with changes in ghrelin, which suggests ghrelin may not be important in meal initiation. AIMSMetformin treatment of Type 2 diabetes is not usually associated with weight gain, and may assist with weight reduction. Plasma ghrelin concentrations are inversely associated with obesity and food intake. Metformin might therefore affect ghrelin concentrations, although previous studies have shown variable results in this regard. The primary aim of this study was to determine the effect of metformin on plasma ghrelin, appetite and satiety in patients with Type 2 diabetes. METHODSEighteen patients with Type 2 diabetes were studied before and after 6 weeks of metformin treatment, which was titrated to 1 g b.d. On the study days patients were fed standard meals of 390 kcal at 08.00 and 12.30 h, plasma samples were collected at 15-and 30-min intervals, and appetite and satiety were measured on visual analogue scales. Changes in the area under the concentration-time curves (AUCs) of plasma ghrelin, insulin, glucose, appetite and satiety were assessed and examined for correlations with metformin AUCs. Changes in fasting adiponectin and leptin were also measured. RESULTSTreatment with metformin increased the mean AUC (07.30-16.30 h) of plasma ghrelin by 24% (P = 0.003), while decreasing those of glucose by 19% (P < 0.001) and insulin by 19% (P = 0.001). No changes were detected in hunger and satiety, or in fasting adiponectin or leptin concentrations. There were no clear correlations between metformin plasma concentrations (AUC) and changes in plasma glucose, insulin or ghrelin.

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“…sured by high-performance liquid chromatography as previously described [29], with limit of quantification 20 mg l -1…”

Section: Laboratory Investigationsmentioning

confidence: 99%

Metformin increases plasma ghrelin in Type 2 diabetes

Doogue¹,

Begg

Moore³

et al. 2009

Brit J Clinical Pharma

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“…In our experience, the algorithm for calculating milk-to-plasma ratio for basic drugs is usually quite robust. Others [27] also observed a similar low milk-to-plasma ratio (0.6) and relative infant dose (0.2%) for metformin and suggested [28] that the low dose might arise if metformin were a substrate for a Pglycoprotein type pump (PGP) located in the breast lobular epithelial cells. However we are unaware of any evidence that metformin is a PGP substrate, or that PGPs exist in breast tissues.…”

Section: Discussionmentioning

confidence: 89%

Transfer of metformin into human milk

et al. 2002

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The concentrations of metformin in breast milk were generally low and the mean infant exposure to the drug was only 0.28% of the weight-normalized maternal dose. As this is well below the 10% level of concern for breastfeeding, and because the infants were healthy, we conclude that metformin use by breastfeeding mothers is safe. Nevertheless, each decision to breastfeed should be made after conducting a risk:benefit analysis for each mother and her infant.

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“…Plasma concentration-time profile after intravenous administration of 25 mg/kg buformin hydrochloride to a rat. (Bonfigli et al, 1999;Zhang et al, 2001) have used buformin as the internal standard. Buformin with a longer butyl side chain eluted later than metformin with a retention time of 19.7 and 15 min in the method of Bonfigli et al and that of Zhang et al, respectively. In our previous studies, we used a bare silica column with reverse-phase eluents for separation and determination of metformin in plasma and in perfusate samples of rat liver (Chou, 2000;Cheng and Chou, 2001).…”

Section: Assay Validationmentioning

confidence: 99%

“…Because of their high polarity, buformin and metformin are difficult to extract directly from plasma with organic solvents, even under strong basic conditions. Simple protein precipitation that uses dilution with equal volume of acetonitrile (Zhang et al, 2001) or 0.5% (w/v) zinc sulfate-1% ehtylene glycol in methanol (Bonfigli et al, 1999;Yamamoto et al, 2002) reduces sensitivity and may not be effective in removing lipophilic endogenous compounds in plasma. In order to overcome these problems, we have used dichloromethane extraction (wash) after protein precipitation of the acidified plasma samples with acetonitrile.…”

Section: Assay Validationmentioning

confidence: 99%

A validated HPLC method with ultraviolet detection for the determination of buformin in plasma

Chou

Cheng

Huang

2004

Biomedical Chromatography

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A sensitive and rapid high-performance liquid chromatographic assay is developed and validated for the determination of buformin in plasma. After addition of metformin as the internal standard, the analytes were deproteinated with acetonitrile, washed with dichloromethane, and the resulting supernatant injected. Chromatography was performed at ambient temperature by pumping a mobile phase of 0.03 m diammonium hydrogen phosphate buffer (pH 7, 250 mL) in methanol (750 mL) at a fl ow rate of 1 mL/min through a silica column. Buformin and metformin were detected at 236 nm, and eluted 9.8 and 15.4 min, respectively. No endogenous substances were found to interfere. Calibration curves were linear over the concentration range of 20-2000 ng/mL. The limit of quantitation was 20 ng/mL. The intra- and inter-day relative standard deviation (RSD) was 8.3%, or less, and the accuracy was within 10.1% of the relative error (RE). The method is suitable in pharmacokinetic investigation of buformin.

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Rapid and simple high-performance liquid chromatographic assay for the determination of metformin in human plasma and breast milk

Cited by 74 publications

References 11 publications

Metformin increases plasma ghrelin in Type 2 diabetes

Metformin increases plasma ghrelin in Type 2 diabetes

Transfer of metformin into human milk

A validated HPLC method with ultraviolet detection for the determination of buformin in plasma

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