Changes in metformin pharmacokinetics after intravenous and oral administration to rats with short‐term and long‐term diabetes induced by streptozotocin

doi:10.1002/jps.21349

Journal of Pharmaceutical Sciences

Volume 97, Issue 12, December 2008, Pages 5363-5375

https://doi.org/10.1002/jps.21349 Get rights and content

Abstract

It has been reported that metformin was primarily metabolized via hepatic CYP2C11, 2D1, and 3A1/2 in rats, and the expression and mRNA levels of hepatic CYP2C11 and 3A1 decreased and increased, respectively, whereas the expression of CYP2D1 was not changed in rat model of diabetes induced by streptozotocin (DMIS). Also minimizing the toxic effects of streptozotocin by carrying out experiments 4–5 weeks after streptozotocin injection has been reported. Thus, the pharmacokinetics of metformin was evaluated in rat model of DMIS at the 7th and the 29th days after streptozotocin injection. After intravenous administration of metformin (100 mg/kg) to rat model of DMIS, the CL_R became significantly faster (46.9% and 77.8% increase for the 7th and the 29th days, respectively; due to urine flow rate‐dependent timed‐interval renal clearance of the drug) and CL_NR became significantly slower (28.0% and 34.3% decrease, respectively; due to decreased hepatic CYP2C11) than in their respective controls. After oral administration of metformin (100 mg/kg) to rat model of DMIS, the AUC became significantly smaller (18.6% and 33.7% decrease for the 7th and the 29th days, respectively) than in their respective controls. The CL_NR of metformin were comparable between two rat models of DMIS. © 2008 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:5363–5375, 2008

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, CL_CR, 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 CL_NR of the drug was negligible; the GI_{24 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)

Y.H. Choi et al.
Dose‐independent pharmacokinetics of metformin after intravenous and oral administration in rats: Hepatic and gastrointestinal first‐pass effects
J Pharm Sci
(2006)
Y.C. Kim 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)
N. Shimojo 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)
T. Borbás et al.
Insulin in flavin‐containing monooxygenase regulation. Flavin‐containing monooxygenase rand cytochrome P450 activities in experimental diabetes
Eur J Pharm Sci
(2006)
C.E. Carnovale et al.
Bile flow decrease and altered bile composition in streptozotocin‐treated rats
Biochem Pharmacol
(1986)
V.F. Price et al.
Strain differences in susceptibility of normal and diabetic rats to acetaminophen hepatotoxicity
Biochem Pharmacol
(1986)
H. Gin et al.
Metformin improved insulin resistance in type I, insulin‐dependent, diabetic patients
Metabolism
(1985)
L. Rossetti et al.
Effect of metformin treatment on insulin action in diabetic rats: In vivo and in vitro correlations
Metabolism
(1990)
S.K. Bae et al.
Pharmacokinetics of oltipraz in rat models of diabetes mellitus induced by alloxan or streptozotocin
Life Sci
(2006)
H.W. Baek et al.
Pharmacokinetics of chlorozoxazone in rats with diabetes: Induction of CYP2E1 on 6‐hydroxychlorzoxazone formation
J Pharm Sci
(2006)

S.K. Bae et al.

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

(2005)

M.M. Bradford

A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein–dye binding

Anal Biochem

(1976)

R.G. Duggleby

Analysis of enzyme progress curves by nonlinear regression

Methods Enzymol

(1995)

F.D. Boudinot et al.

Fluid shifts and other factors affecting plasma protein binding of prednisolone by equilibrium dialysis

J Pharm Sci

(1984)

A.J. Scheen

Clinical pharmacokinetics of metformin

Clin Pharmacokinet

(1996)

C.R. Sirtori et al.

Disposition of metformin (N^,N‐dimethylbiguanide) in man

Clin Pharmacol Ther

(1978)

G.T. Tucker et al.

Metformin kinetics in healthy subjects and in patients with diabetes mellitus

Br J Clin Pharmacol

(1981)

Y.H. Choi et al.

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

(2006)

T. Sakuma et al.

Different expression of hepatic and renal cytochrome P450s between the streptozotocin‐induced diabetic mouse and rat

Xenobiotica

(2001)

Cited by (27)

Comparative pharmacokinetics of arctigenin in normal and type 2 diabetic rats after oral and intravenous administration
2015, Fitoterapia
Citation Excerpt :
Notably, there are opposite reports in the literature on the effects of diabetes mellitus on the oral pharmacokinetics of drugs in STZ-induced animals. Choi indicated that the AUC of metformin became significantly smaller than the relative controls after oral administration [23], whereas Liu found that diabetic condition significantly increased the AUC of baicalin following oral dosing [24]. The explanation for these conflicting results is that diabetes is a complex endocrine metabolic disorder which may result in the alteration of the activity and expression of cytochromes P450, ATP-binding cassette (ABC) drug transporters or others [10,16,24].
Arctigenin is the main active ingredient of Fructus Arctii for the treatment of type 2 diabetes. In this study, the pharmacokinetics of arctigenin in normal and type 2 diabetic rats following oral and intravenous administration was investigated. As compared to normal rats, C_max and AUC_0–10h values of oral arctigenin in diabetic rats increased by 356.8% and 223.4%, respectively. In contrast, after intravenous injection, the C_max and AUC_0–10h values of arctigenin showed no significant difference between diabetic and normal rats. In order to explore how the bioavailability of oral arctigenin increased under diabetic condition, the absorption behavior of arctigenin was evaluated by in situ single-pass intestinal perfusion (SPIP). The results indicated that arctigenin was a substrate of P-glycoprotein (P-gp). The absorption difference of arctigenin in the normal and diabetic rats could be eliminated by the pretreatment of classic P-gp inhibitor verapamil, suggesting that P-gp might be the key factor causing the absorption enhancement of arctigenin in diabetic rats. Further studies revealed that the uptake of rhodamine 123 (Rho123) in diabetic rats was significantly higher, indicating that diabetes mellitus might impair P-gp function. Consistently, a lower mRNA level of P-gp in the intestine of diabetic rats was found. In conclusion, the absorption of arctigenin after oral administration was promoted in diabetic rats, which might be partially attribute to the decreased expression and impaired function of P-gp in intestines.
Increased levels of fatty acids contributed to induction of hepatic CYP3A4 activity induced by diabetes - In vitro evidence from HepG2 cell and Fa2N-4 cell lines
2014, Journal of Pharmacological Sciences
Accumulating evidences have shown that diabetes upregulated the function and expression of CYP3A4, but the mechanism remained unclear. In this study, HepG2 cells were incubated with serum from diabetic rats induced by streptozotocin, and the activity of CYP3A4 was measured by substrate metabolism. Results showed that incubation with diabetic serum significantly induced CYP3A4 activity in HepG2 cells. To identify the specific factors contributing to the regulation, the abnormally altered components in diabetic serum, including glucose, insulin, cholesterol, and free fatty acids were screened. It was found that only fatty acids concentration-dependently up-regulated CYP3A4 activity, and the induction by fatty acids was further confirmed in Fa2N-4 cells. Data from western blotting and QT-PCR showed that induction of CYP3A4 activity was associated with up-regulation of CYP3A4 protein and mRNA levels. In addition, effects of pharmacological inhibitors on fatty acid–induced CYP3A4 activity were studied. The results indicated that the induction of CYP3A4 activity by oleic acid may be partly via AMPK-, PKC-, and NF-κB–dependent pathways, whereas that by palmitic acid was possibly associated with the PKC-dependent pathway. In conclusion, the increased levels of fatty acids may be one of the reasons leading to the elevated function and expression of CYP3A4 under diabetic conditions.
Effects of Korean red ginseng extract on acute renal failure induced by gentamicin and pharmacokinetic changes by metformin in rats
2013, Food and Chemical Toxicology
Citation Excerpt :
A plasma sample was collected to measure total protein, albumin, urea nitrogen, glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), and creatinine levels (analyzed by Green Cross Reference Lab., Seoul, South Korea). Procedures used for pretreating the rats including cannulation (early in the morning at the end of week 4) of the carotid artery and jugular vein were similar to a method reported previously (Choi and Lee, 2006; Choi et al., 2006, 2008). The rats were not restrained during the experimental period in these studies.
Korean red ginseng is one of the best selling dietary supplements and its individual constituents enhance renal function. Acute renal failure (ARF) is a predisposing complication of diabetes mellitus as a result of combination drug therapy. The combination of antibiotic–antidiabetic drugs can entail toxicities and drug interactions because of the antibiotic resistance in patients with severe bacterial infection. Currently, gentamicin–metformin combination therapy is commonly prescribed for treating bacterial infections and diabetes, even though both drugs are mainly excreted via the kidney. Thus, this study was designed to investigate whether a Korean red ginseng extract (KRG) prevents renal impairment and pharmacokinetic changes by metformin in rats with renal failure induced by gentamicin.
The in vivo pharmacokinetics and in vitro hepatic/intestinal metabolism of metformin were assessed using control (CON), control with Korean red ginseng extract (KRG-CON), acute renal failure induced by gentamicin (ARF), and ARF with Korean red ginseng (KRG-ARF) rats.
Pharmacokinetic changes of metformin did not occur in KRG-ARF rats because KRG reduce the renal accumulation of gentamicin compared to ARF rats. Thus, KRG seemed to prevent acute renal failure induced by gentamicin treatment.
Slower clearance of intravenous metformin in rats with acute renal failure induced by uranyl nitrate: Contribution of slower renal and non-renal clearances
2010, European Journal of Pharmaceutical Sciences
It has been reported that metformin was primarily metabolized via hepatic CYP2C11, 2D1, and 3A1/2 in rats. It has also been reported that the protein expression and/or mRNA levels of hepatic CYP2C11, 2D subfamily, and 3A1 have decreased, decreased, and increased, respectively, in U-ARF rats. Thus, pharmacokinetic changes of intravenous metformin in U-ARF rats were evaluated. Metformin was administered intravenously at a dose of 50 mg/kg to control and U-ARF rats. After i.v. administration of metformin to U-ARF rats, its time-averaged total body clearance was significantly slower (95.2% decrease) than controls. This could have been due to both significantly slower time-averaged renal clearance (99.1% decrease; due to a urine flow rate-dependent timed-interval renal clearance of the drug, a decrease in renal OCT2, and/or an impaired kidney function in U-ARF rats) and time-averaged non-renal clearance (83.8% decrease; due to a decrease in hepatic CYP2C11 and 2D subfamily in U-ARF rats).
Pharmacokinetics of ipriflavone and its two metabolites, M1 and M5, after the intravenous and oral administration of ipriflavone to rat model of diabetes mellitus induced by streptozotocin
2009, European Journal of Pharmaceutical Sciences
Ipriflavone was reported to be primarily metabolized via hepatic cytochrome P450 (CYP) 1A1/2 and 2C11 in male Sprague–Dawley rats. The protein expression and/or mRNA levels of hepatic CYP1A subfamily and 2C11 was reported to be increased and decreased, respectively, in diabetic rats induced by streptozotocin (DMIS rats). Thus, the pharmacokinetic parameters of ipriflavone and its two metabolites, M1 and M5, were compared after the i.v. (20 mg/kg) and p.o. (200 mg/kg) administration of ipriflavone to control and DMIS rats. After both i.v. and p.o. administration of ipriflavone to DMIS rats, the AUCs of ipriflavone were significantly smaller (by 31.7% and 34.2% for i.v. and p.o. administration, respectively) than controls. The faster Cl_nr (smaller AUC) of i.v. ipriflavone could have been due to the faster hepatic Cl_int (because of an increase in the protein expression and/or mRNA level of hepatic CYP1A subfamily) and the faster hepatic blood flow rate than controls. The smaller AUC of p.o. ipriflavone in DMIS rats could have mainly been due to the faster intestinal Cl_int (because of an increase in the intestinal CYP1A subfamily) than controls.
Metformin primarily decreases plasma glucose not by gluconeogenesis suppression but by activating glucose utilization in a non-obese type 2 diabetes Goto-Kakizaki rats
2009, European Journal of Pharmacology
Metformin is an anti-diabetic agent that has been reported to decrease plasma glucose by multiple mechanisms, such as decreasing hepatic glucose production and activating peripheral glucose utilization. In order to elucidate the primary glucose-lowering mechanism of metformin, the present study focused on a comparison of the acute effect between metformin and CS-917 as a direct gluconeogenesis inhibitor. We examined the effect of metformin and CS-917 on glucose turnover in intravenous glucose-loaded Goto-Kakizaki (GK) rats, and on gluconeogenesis and glucose utilization in rat hepatocytes. Moreover, the glucose-lowering effect of metformin and CS-917 was compared in a fed and a fasted state in GK rats.
In intravenous glucose-loaded GK rats, metformin and CS-917 lowered plasma glucose by increasing the glucose disappearance rate and by decreasing the glucose appearance rate, respectively.
In rat hepatocytes, CS-917 but not metformin suppressed gluconeogenesis (IC₅₀ = 0.136 µM). Instead, metformin dose-dependently increased glucose uptake and the following lactate production at 30 to 100 µM.
Metformin decreased plasma glucose more in a fed state than in a fasted state in GK rats. CS-917, however, decreased plasma glucose more in a fasted state.
These results confirm that metformin primarily decreases plasma glucose not by gluconeogenesis inhibition but by activating glucose utilization in GK rats. Moreover, metformin and CS-917 have different glucose-lowering effects depending on the nutrient state, which may be related to differences in their mechanisms of action. Such differences in action may have implications for metformin and CS-917 in the treatment of type 2 diabetes patients.

View all citing articles on Scopus

View full text

Research ArticlesChanges in metformin pharmacokinetics after intravenous and oral administration to rats with short‐term and long‐term diabetes induced by streptozotocin

Abstract

Section snippets

INTRODUCTION

Chemicals

Preliminary Study

DISCUSSION

Acknowledgements

J Pharm Sci

Eur J Pharm Sci

Biochem Pharmacol

Eur J Pharm Sci

Biochem Pharmacol

Biochem Pharmacol

Metabolism

Metabolism

Life Sci

J Pharm Sci

Eur J Pharm Sci

Anal Biochem

Methods Enzymol

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

Research Articles
Changes in metformin pharmacokinetics after intravenous and oral administration to rats with short‐term and long‐term diabetes induced by streptozotocin

Disposition of metformin (N^,N‐dimethylbiguanide) in man