Research ArticlesChanges in metformin pharmacokinetics after intravenous and oral administration to rats with short‐term and long‐term diabetes induced by streptozotocin
Section snippets
INTRODUCTION
Metformin, a biguanide antihyperglycemic agent, has widely been used in the management of type 2 diabetes mellitus; it lowers blood glucose concentration without causing hypoglycemia.1 After intravenous (at doses of 0.25–1.0 g) and oral (at doses of 0.5–1.5 g) administration of metformin to four healthy volunteers, the terminal half‐lives were 1.52–4.50 h, percentages of the dose excreted in the urine (via active renal tubular secretion) were 78.9–99.9%, absorption was not complete (20–30% of
Chemicals
Metformin hydrochloride and ipriflavone [an internal standard for the high‐performance liquid chromatographic (HPLC) analysis of metformin] were donated by Daelim Medical (Seoul, South Korea) and Research Laboratory of Dong‐A Pharmaceutical Company (Yongin, South Korea), respectively. The reduced form of β‐nicotinamide adenine dinucleotide phosphate (NADPH, as a tetrasodium salt), tri(hydroxymethyl)aminomethane (Tris)‐buffer, ethylendiamine tetraacetatic acid (EDTA), and streptozotocin were
Preliminary Study
Body weight, blood glucose levels, 12‐h urine output, plasma chemistry data, CLCR, and relative liver and kidney weights in rat model of DMIS at the 7th and the 29th days, and their respective controls are listed in Table 1. In rat model of DMIS at the 7th and the 29th days, the plasma levels of albumin became significantly lower (16.4% and 15.1% decrease, respectively), GOT (154% and 122% increase, respectively) and GPT (151% and 440% increase, respectively) became significantly higher, and
DISCUSSION
Induction of diabetes mellitus in rats by streptozotocin was evident based on significantly higher blood glucose levels, decreased final body weight (body weight gain), and increased 12‐h (or 24‐h) urine output (Tabs. 1,3, and 4).
Contribution of gastrointestinal (including biliary) excretion of unchanged metformin to the CLNR of the drug was negligible; the GI24 h values were 1.36%, 1.75%, 3.02%, and 1.05% of the intravenous dose for rat model of DMIS at the 7th day and their controls and rat
Acknowledgements
This study was supported in part by a grant from the Seoul City Collaborative Project among the Industry, Academy, and Research Institute, Korea.
REFERENCES (39)
- et al.
Dose‐independent pharmacokinetics of metformin after intravenous and oral administration in rats: Hepatic and gastrointestinal first‐pass effects
J Pharm Sci
(2006) - et al.
Pharmacokinetics of theophylline in diabetes mellitus rats: Induction of CYP1A2 and CYP2E1 on 1,3‐dimethyluric acid formation
Eur J Pharm Sci
(2005) - et al.
Changes in amounts of cytochrome P450 isozymes and levels of catalytic activities in hepatic and renal microsomes of rats with streptozotocin‐induced diabetes
Biochem Pharmacol
(1993) - et al.
Insulin in flavin‐containing monooxygenase regulation. Flavin‐containing monooxygenase rand cytochrome P450 activities in experimental diabetes
Eur J Pharm Sci
(2006) - et al.
Bile flow decrease and altered bile composition in streptozotocin‐treated rats
Biochem Pharmacol
(1986) - et al.
Strain differences in susceptibility of normal and diabetic rats to acetaminophen hepatotoxicity
Biochem Pharmacol
(1986) - et al.
Metformin improved insulin resistance in type I, insulin‐dependent, diabetic patients
Metabolism
(1985) - et al.
Effect of metformin treatment on insulin action in diabetic rats: In vivo and in vitro correlations
Metabolism
(1990) - et al.
Pharmacokinetics of oltipraz in rat models of diabetes mellitus induced by alloxan or streptozotocin
Life Sci
(2006) - et al.
Pharmacokinetics of chlorozoxazone in rats with diabetes: Induction of CYP2E1 on 6‐hydroxychlorzoxazone formation
J Pharm Sci
(2006)
Pharmacokinetic changes of DA‐7867, a new oxazolidinone, after intravenous and oral administration to rats with short‐term and long‐term diabetes mellitus induced by streptozotocin
Eur J Pharm Sci
A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein–dye binding
Anal Biochem
Analysis of enzyme progress curves by nonlinear regression
Methods Enzymol
Fluid shifts and other factors affecting plasma protein binding of prednisolone by equilibrium dialysis
J Pharm Sci
Clinical pharmacokinetics of metformin
Clin Pharmacokinet
Disposition of metformin (N,N‐dimethylbiguanide) in man
Clin Pharmacol Ther
Metformin kinetics in healthy subjects and in patients with diabetes mellitus
Br J Clin Pharmacol
Effects of enzyme inducers and inhibitors on the pharmacokinetics of metformin in rats: Involvement of CYP2C11, 2D1, and 3A1/2 for the metabolism of metformin
Br J Pharmacol
Different expression of hepatic and renal cytochrome P450s between the streptozotocin‐induced diabetic mouse and rat
Xenobiotica
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