Metformin In Rats Research Articles

Hepatic and skeletal muscle glycogen content in rats treated with metformin and submitted to acute exercise by swimming

O objetivo deste estudo foi avaliar o comportamento das reservas glicogênicas de ratos, submetidos a uma condição de exercício agudo (50 minutos de natação na intensidade leve), após o tratamento com metformina. Quarenta ratos Wistar (180-200g) adultos foram divididos em quatro grupos (tratados ou não por quinze dias) e assim representados: Controle; Exercício agudo por natação (realizaram uma sessão de natação, sendo 50 minutos na intensidade leve); Tratado com metformina (receberam o fármaco metformina na dosagem de 1,4 mg/ml, durante o período experimental; Tratados com metformina e submetidos a condição exercício agudo por natação (receberam o fármaco metformina na dosagem de 1,4 mg/ml e realizaram uma sessão de natação, sendo 50 minutos na intensidade leve). O exercício agudo diminuiu as reservas glicogênicas, já os animais tratados com metformina, apresentaram um aumento em suas reservas glicogênicas musculares e hepáticas em relação ao grupo que realizou o exercício sem suplementação (p0,05). O tratamento com metformina promoveu melhora nas condições energéticas e menor resposta ao estresse, sugerindo ser uma importante ferramenta farmacológica para a potencialização da performance.

The effects of goutweed (Aegopodium Podagraria L.) preparations and their combinations with metformin in rats with the disorders of the lipid and carbohydrate metabolism induced by protamine sulphate

The improvement of the therapy of the metabolic syndrome, obesity, and type 2 diabetes is an important task which may be realized through the co-administration of herbal and synthetic medicines. The tincture and extract obtained from the aerial part of goutweed (Aegopodium podagraria L.) have been shown to possess antidiabetic and organoprotective properties. Goutweed tincture exerts a permissive effect on the action of metformin in dexamethasone-treated diabetic rats. Aim. The objective of this study is to determine the efficacy of the combined use of goutweed tincture and extract with metformin on the model of the primary disorder of the lipid metabolism. Materials and Methods. The model was used that presupposed administration of protamine sulfate to rats (10 mg/kg per day intramuscularly) against the background of atherogenic diet with the additional administration of cholestrol. Goutweed extract and tincture (1 g/kg and 1 ml/kg intragastrically, respectively), metformin (50 mg/kg intragastrically) and their combinations were administered during the whole period of model development. The lipid composition of the liver and blood plasma, as well as the content of glycogen in the liver were studied, and, as this model is accompanied with insulin resistance, glucose tolerance test was carried out. Results. It has been shown that all studied drugs and their combinations normalize the lipid composition of the liver, reducing the content of cholesterol and triglycerides and increasing the level of phospholipids. They do not significantly influence on the lipid spectrum of the blood plasma, tend to elevate the level of liver glycogen, their efficacy does not change in combined use. Goutweed tincture and metformin in combination, but not per se, completely normalize area under glucose curve that is significantly increased in the untreated group, the extract does not change this value. Conclusions. Goutweed extract and tincture normalize the lipid composition of the liver in rats with lipid and carbohydrate metabolism disorders caused by protamine sulfate and atherogenic diet, the tincture also exerts a permissive effect on the action of metformin on glucose metabolism, but not on lipid metabolism. (For citation: Tovchiga OV, Gorbatch TV, Shtrygol’ SYu, et al. The effects of goutweed (Aegopodium podagraria L.) preparations and their combinations with metformin in rats with the disorders of the lipid and carbohydrate metabolism induced by protamine sulphate. Reviews on Clinical Pharmacology and Drug Therapy. 2017;15(2):31-41. doi: 10.17816/RCF15231-41).

Pharmacokinetics of metformin in the rat: assessment of the effect of hyperlipidemia and evidence for its metabolism to guanylurea.

Metformin pharmacokinetics are highly dependent upon organic cationic transporters. There is evidence of a change in its renal clearance in hyperlipidemic obese patients, and no information on its metabolic fate. To study some of these aspects, the influence of poloxamer 407 (P407)-induced hyperlipidemia on metformin pharmacokinetics was assessed. Control and P407-treated adult male rats were administered 30 mg/kg metformin intravenously (i.v.). The pharmacokinetic assessments were performed at 2 time points, 36 and 108 h, following the intraperitoneal dose of P407 (1 g/kg). mRNA and protein expressions of cationic drug transporters were also measured. There was no evidence of a change in metformin pharmacokinetics after i.v. doses as a consequence of short-term hyperlipidemia, and a change in transporter mRNA but not protein expression was observed in the P407- treated rats 108 h after P407 injection. Urinary recovery of unchanged drug was high (>90%) but incomplete. Presumed metabolite peaks were detected in chromatograms of hepatocytes and microsomal protein spiked with metformin. Comparative chromatographic elution times and mass spectra suggested that one of the predominant metabolites was guanylurea. Hyperlipidemia by itself did not affect the pharmacokinetics of metformin. Guanylurea is a putative metabolite of metformin in rats.

Potential involvement of JNK1 repression in the hepatic effect of sitagliptin and metformin in rats subjected to high fat diet and chronic mild distress

BackgroundDepression and non-alcoholic steatohepatitis (NASH) are highly co-morbid, and hepatic JNK pathway may be involved in their relation. AimTo evaluate the impact of depression on NASH through the involvement of JNK1 and to assess the effect of sitagliptin and metformin on hepatic JNK1 expression in both NASH and NASH associated with depression. MethodsEight groups of male Wistar rats were used: naïve rats, non-stressed NASH, non-stressed NASH sitagliptin treated, non-stressed NASH metformin treated, stressed, stressed NASH untreated, stressed NASH sitagliptin treated and stressed NASH metformin treated. Behavioral, biochemical, molecular and histopathological studies were performed. ResultsNon-stressed NASH group showed depressive like symptoms, disturbed glucose homeostasis, impairment of liver functions, decrease adiponectin and increase malondialdehyde, which were aggreviated by stress.Sitagliptin produced significant improvement compared to metformin regarding biochemical and histopathological parameters. Furthermore, sitagliptin significantly decreased expression of hepatic JNK1 in both stressed and non-stressed rats. All these changes were accompanied by significant improvement of behavioral changes. ConclusionsThe link between NASH and depression raised the role of JNK activation through increase expression of JNK1. Since sitagliptin was associated with preferable effects than metformin, therefore, it is potentially preferred in the management of either NASH or NASH associated with depression.

Metoprolol decreases the plasma exposure of metformin via the induction of liver, kidney and muscle uptake in rats.

Drug interactions are one of the commonest causes of side effects, particularly in long-term therapy. The aim of the current study was to investigate the possible effects of metoprolol on the pharmacokinetics of metformin in rats and to clarify the mechanism of drug interaction. In this study, rats were treated with metformin alone or in combination with metoprolol. Plasma, urine and tissue concentrations of metformin were determined by HPLC. Western blotting and real-time qPCR were used to evaluate the expression of rOCTs and rMATE1. The results showed that, after single or 7-day repeated administration, the plasma concentrations of metformin in the co-administration group were significantly decreased compared with that in the metformin group. However, the parameter V/F of metformin in the co-administration group was markedly increased compared with that in the metformin group. The hepatic, renal and muscular Kp of metformin were markedly elevated after co-administration with metoprolol. Consistently, metformin uptake in rat kidney slices was significantly induced by metoprolol. In addition, multiple administrations of metoprolol significantly reduced the expression of rMATE1 in rat kidney as well as the urinary excretion of metformin. Importantly, after long-term administration, lactic acid and uric acid levels in the co-administration group were increased by 25% and 26%, respectively, compared with that in the metformin group. These results indicate that metoprolol can decrease the plasma concentration of metformin via the induction of hepatic, renal and muscular uptake, and long-term co-administration of metformin and metoprolol can cause elevated lactic acid and uric acid levels. Copyright © 2016 John Wiley & Sons, Ltd.

Abstract P3-11-04: Metabolic profiles in female Sprague-Dawley rats receiving either a standard (4% fat) or Western (20% fat) diet and changes in rats bearing mammary cancers

Abstract The methylnitrosourea(MNU)-induced model of ER+ mammary cancers in female Sprague-Dawley rats has been routinely used in our laboratories for screening chemopreventive agents. We recently reported that metformin was ineffective in preventing mammary cancers in this model when given to rats on a standard diet (Thompson, et al, Cancer Prev Res. 2015;8:231-9). In this study, we evaluated metformin in rats placed on either standard diet (4% fat) or a Western diet (20% fat, low calcium). As fat calories, these diets were 8% and 42%, respectively. The rats were placed on standard diet or Western diet at 43 days of age, given MNU (via the jugular vein) once at 50 days of age, and administered metformin or vehicle at 57 days of age for the remainder of the study. Serum of the rats in the various groups was obtained at 78 days of age, and at the end of the study (when mammary tumors were present). The levels of approximately 500 metabolites were compared in the serum based on data obtained by Metabolon (Research Triangle Park, NC). These studies showed that each of the four groups [(standard diet (early and late) or Western diet (early and late)] yielded four clearly distinct patterns based on an unsupervised principal component analysis. Certain of the metabolites which were differentially expressed in serum from standard vs Western diets at the early time point were alpha-10-undecanoate, 13-methylmyristic acid, 4-hydroxy-benzoate, 2-amino-heptanpate, tocopherol, and nicotinamide. Certain of these were fatty acids and lipid soluble vitamins that one would expect to be altered. Comparing serum from standard vs Western diets at the late time point confirmed many of these metabolic differences. We also compared serum from the early and late time points since the latter serums were typically from animals with a significant number of mammary cancers. We observed a number of metabolite changes including 4-hydroxy-butyrate, acetyl-carnitine, oxalate, and threonate. These cancer- related profiles will be discussed at greater lengths. Altered profiles caused by the administration of metformin and other chemopreventive agents will also be discussed. Of interest, metformin was consistently ineffective in preventing mammary cancers in rats given either standard or Western diet. Supported by NCI contract HHSN261201200021I. Citation Format: Thompson MD, Grubbs CJ, Moeinpour F, Steele VE, Miller MS, Lubet RA. Metabolic profiles in female Sprague-Dawley rats receiving either a standard (4% fat) or Western (20% fat) diet and changes in rats bearing mammary cancers. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-11-04.

Investigation of possible pharmacokinetic interaction of metformin with sugar replacement sweeteners in rats

Metformin is widely used for type II diabetes. Sugar replacement sweeteners such as Aspartame and Stevia, are usually consumed concomitantly with other antidiabetics by patients The aim of this work is to investigate possible effects of two types of sweeteners; stevia and aspartame on the pharmacokinetic parameters of metformin in rats. A simple, validated bio-analytical HPLC method was developed to measure metformin in rat plasma. Three groups of rats, each of eight were subjected to this study. The first group was given metformin solution 20mg/kg alone , the second group was given 20 mg/kg metformin with 4mg/kg stevia and the third group was given 20 mg/kg metformin with 10 mg/kg aspartame on fasting state. Blood samples were taken on scheduled time interval up to 6 hours and analyzed for metformin concentration. Pharmacokinetic parameters were calculated by Non-Compartmental Model and data were interpreted. The results showed that administration of these two sweeteners did not have high effect on pharmacokinetics of metformin.

Cardioprotective effect of metformin against doxorubicin cardiotoxicity in rats.

Objective:The clinical use of doxorubicin, which is a strong antineoplastic agent, is limited due to its cardiotoxic side effects. Metformin is a drug with antihyperglycemic effects, and it has been shown to have a cardioprotective effect on left ventricular function in experimental animal models of myocardial ischemia. The present study investigated the cardioprotective effect of metformin in rats with doxorubicin cardiotoxicity.Methods:Wistar albino rats were used in the study. Forty male, 10-week-old Wistar albino rats were randomly divided four groups. The control group rats were intraperitoneally administered saline solution twice a week, four doses in total. The doxorubicin group rats received doxorubicin (4 mg/kg, twice a week, cumulative dose: 16 mg/kg) intraperitoneally. The metformin group rats received metformin (250 mg/kg/day, every day for 14 days) via gavage. The doxorubicin + metformin group rats received doxorubicin and metformin at the same dose. Left ventricular functions were evaluated by using M-mode echocardiography one day after the last dose of doxorubicin. Heart tissue samples were histopathologically examined. Cardiomyocyte apoptosis was detected using in situ terminal deoxynucleotide transferase assay (TUNEL). Serum brain natriuretic peptide and C-type natriuretic peptide levels were measured. Catalase, superoxide dismutase, glutathione peroxidase, and tumor necrosis factor alpha levels were analyzed in the heart tissue. The assumptions of equality of variances and normal distribution were checked for all variables (Shapiro-Wilk test and Q-Q graphics). To identify intergroup differences, one-way variant analysis or the Kruskal-Wallis test was used. A p<0.05 value was accepted as statistically significant.Results:Our results showed that doxorubicin treatment caused significant deterioration in left ventricular functions by echocardiography, histological heart tissue damage, and increase in cardiomyocyte apoptosis. Doxorubicin + metformin group showed protection in left ventricular function, elimination of histopathologic change, and reduced of cardiomyocyte apoptosis.Conclusion:The present study provided evidence that metformin has cardioprotective effects against doxorubicin cardiotoxicity.

Gender-Related Differences in the Expression of Organic Cation Transporter 2 and its Role in Urinary Excretion of Metformin in Rats.

Organic cation transporter 2 (rOCT2) and multidrug and toxin extrusion protein 1 (rMATE1) are mainly expressed in rat renal proximal tubules and mediate urinary excretion of cationic drugs, such as metformin. Accumulated evidence indicated that renal rOCT2 expression in male rats is much higher than that of female rats. However, it is unclear whether the gender-related differences in rOCT2 expression between male and female rats can affect the urinary excretion of metformin. The aim of this study was to investigate the effect of gender on the pharmacokinetics of metformin and to clarify the effect of gender-related differences on renal rOCT2 expression and its role in urinary excretion of metformin. Renal rOCT2 levels, but not rOCT1 and rMATE1, were significantly lowered in female rats when compared to that of male rats (P<0.01), while the pharmacokinetic parameters, i.e., AUC0→t, t 1/2, CL/F, and cumulative urinary excretion of metformin, did not show any significant differences between female and male rats following oral administration of metformin at l00mg/kg (P>0.05). However, when metformin was orally administered at the dose of 500mg/kg, the cumulative urinary excretion and renal tissue-to-plasma concentration ratio of metformin in female rats (26,689±1266μg and 2.96±0.47mL/g, respectively) were markedly lowered compared to that of male rats (32,949±1384μg and 4.20±0.31mL/g, respectively), and the plasma concentration of metformin in female rats (55.9±4.5μg/mL) was significantly increased compared to that of male rats (43.5±3.1μg/mL) at 2h after oral administration. These results indicated that effect of gender-related differences on renal rOCT2 expression indeed contributes to the decreased urinary excretion of metformin in female rats when metformin was administered at relatively high doses.

Assessment of Pharmacodynamic and Pharmacokinetic Interaction of Aqueous Extract of Cassia auriculata L. and Metformin in Rats.

Background:Cassia auriculata L. (CA) leaf extract might increase the body's production of insulin thereby suppressing the elevated blood glucose and lipid levels in diabetic rats. CA has been used as dietary supplement in India from ancient times.Objective:The present study was to elucidate the synergistic pharmacodynamic (PD) and pharmacokinetic (PK) interaction of metformin (MT) with CA.Materials and Methods:A simple, precise reverse phase high performance liquid chromatography - UV detection mode method was developed to quantify MT in rat plasma. In PD interaction, streptozotocin (45mg/kg, intraperitoneally) induced diabetic Wistar rats weighing 180–250 g of either sex were randomized to receive MT (90 mg/kg, MT-HD), CA (500 mg/kg) separately and in combination of MT (90 mg/kg, MT-HD) + CA (500 mg/kg), and MT (45 mg/kg, MT-LD) + CA (500 mg/kg) (all oral) along with normal and diabetic control groups for 21 days. PK of MT was carried out in normal rats with preadministration of CA (500 mg/kg) for 14 days.Results:PD data showed reasonable blood glucose lowering effect of CA. The reduction of MT dose with combination of CA achieved a similar blood glucose lowering effect of MT alone. PK data showed enhanced time taken to achieve maximum plasma concentration (Cmax), area under the curve (AUC0-t), and Cmax in combination group of MT (90mg/kg) and CA (500mg/kg), and reduction of MT dose in Group III had a reduced Cmax and AUC0-t compared to MT alone treated groups.Conclusion:Co-administration of CA with MT at varying dose showed a synergistic herb-drug interaction. Thus using the synergistic herb-drug interaction, the dose level of MT may be reduced to produce the same therapeutic effect as when taken alone.SUMMARY Elucidating the synergistic pharmacodynamic (PD) and pharmacokinetic (PK) interaction of metformin (MT) with Cassia auriculata L. (CA)PD data showed reasonable blood glucose lowering effect of CA. The reduction of MT dose with combination of CA achieved a similar blood glucose lowering effect of MT alonePK data showed enhanced time taken to achieve maximum plasma concentration (Cmax), area under the curve (AUC0-t), and Cmax in combination group of MT and CA, and reduction of MT dose had a reduced Cmax and AUC0-t compared to MT alone treated groupsCo-administration of CA with MT at varying dose showed a synergistic herb-drug interaction. Thus using the synergistic herb-drug interaction, the dose level of MT may be reduced to produce the same therapeutic effect as when taken alone. Abbreviations used: CA: Cassia auriculata L., PD: Pharmacodynamic, PK: Pharmacokinetic, MT: Metformin, RP-HPLC-UV: Reverse phase High Performance Liquid Chromatography-UV detection mode, Tmax: Time taken to achieve maximum plasma concentration, AUC0-t: Area under the curve, Cmax: Maximum plasma concentration.

Organic cation transporter-mediated drug-drug interaction potential between berberine and metformin.

Berberine, the main active component of the herbal medicine Rhizoma Coptidis, has been reported to have hypoglycemic and insulin-sensitizing effects and, therefore, could be combined with metformin therapy. Thus, we assessed the potential drug-drug interactions between berberine and metformin. We investigated the in vitro inhibitory potency of berberine on metformin uptake in HEK293 cells overexpressing organic cation transporter (OCT) 1 and 2. To investigate whether this inhibitory effect of berberine on OCT1 and OCT2 could change the pharmacokinetics of metformin in vivo, we measured the effect of berberine co-administration on the pharmacokinetics of metformin at a single intravenous dose of 2mg/kg metformin and 10mg/kg berberine. In HEK293 cells, berberine inhibited OCT1- and OCT2-mediated metformin uptake in a concentration dependent manner and IC50 values for OCT1 and OCT2 were 7.28 and 11.3μM, respectively. Co-administration of berberine increased the initial plasma concentration and AUC of metformin and decreased systemic clearance and volume of distribution of metformin in rats, suggesting that berberine inhibited disposition of metformin, which is governed by OCT1 and OCT2. Berberine inhibited the transport activity of OCT1 and OCT2 and showed significant potential drug-drug interactions with metformin in in vivo rats.

Abstract 275: High Fat Diet-induced Decreases In Insulin Signaling In Afferent Renal Nerves Are Prevented By Intrathecal Injection Of Metformin In Rats

Metformin, an anti-type 2 diabetic agent that increases insulin sensitivity in target tissues, has been suggested having neuroprotective effects. Our previous data showed that metformin protects against high fat diet (HFD)-induced impairment in renal afferent nerves that express the transient receptor potential vanilloid 1 (TRPV1) channels, and prevents HFD-induced renal functional deterioration and hypertension. However, mechanisms of metformin-mediated neuroprotection are largely unknown. This study tests the hypothesis that HFD impairs insulin signaling in afferent renal nerves, which is prevented by metformin via the pathway of IRS-1-tyr, AMPK, and GLUT-1/3. Metformin (1 ng/kg, daily intrathecal injection via indwelled catheters to segments T8-L3 supplying the kidneys) or vehicle was given to rats fed a HFD or normal fat diet (Con) for 8 weeks. Immunohistochemical staining showed that insulin receptor substrate-1 phosphorylated with serine (p-IRS-1-ser), insulin receptor substrate-1 phosphorylated with tyrosine (p-IRS-1-tyr), phosphorylated AMP-activated protein kinase (p-AMPK), glucose transporter 1 (GLUT-1), and GLUT-3 were expressed in dorsal root ganglia (DRG). Levels of p-IRS-1-ser were increased by HFD but decreased by metformin in Con rats, and HFD-induced increases in p-IRS-1-ser were prevented by metformin. Levels of p-IRS-1-tyr, p-AMPK, and the trafficking of GLUT-1 and GLUT-3 from cytoplasma to cell membrane in DRG were decreased by HFD but increased by metformin in Con rats, and HFD-induced decreases in these parameters were prevented by metformin (p-IRS-1-tyr, Con: 0.23±0.02, Con+Met: 0.34±0.04, HFD: 0.14±0.02, HFD+Met: 0.22±0.03, p&lt;0.05). Afferent renal nerve activity (ARNA) in response to insulin perfusion into the renal pelvis was decreased by HFD but enhanced by metformin in Con rats, and HFD-induced decreases in ARNA was prevented by metformin. Our data showed that HFD decreases insulin signaling in afferent renal nerves, which is prevented by metformin injected intrathecally to segments innervating kidneys. These data indicate that metformin may constitute neuroprotecitve effects via improving insulin signaling in afferent renal nerves via activation of the pathway of IRS-1-tyr, AMPK, and GLUT-1/3.

Effects of single or repeated Yukmijihwang-tang administration, a polyherbal formula, on pharmacokinetics of metformin in rats

Effects of single or repeated Yukmijihwang-tang administration, a polyherbal formula, on pharmacokinetics of metformin in rats

Role of age-related decrease of renal organic cation transporter 2 in the effect of atenolol on renal excretion of metformin in rats.

Many diabetes patients, especially the elder ones, suffered from hypertension simultaneously. Therefore, it is very likely that a large number of diabetes patients receiving metformin hydrochloride may simultaneously be given beta-blockers. Knowing that both metformin and atenolol are eliminated by organic cation transporter 2 (OCT2/SLC22A2) expressed in the renal basolateral membrane, it is not clear whether there is a competitive effect on the renal excretion of metformin and/or atenolol when metformin and atenolol were co-administered, and whether age was involved in this drug-drug interaction. In this present study, both young rats (aged 3 months) and aged rats (aged 12 months) were used, rats were divided into metformin-treated group and metformin and atenolol co-administrated group, respectively. Either metformin (2.5 mg/kg) alone or metformin (2.5 mg/kg) in combination with atenolol (8 mg/kg) was administered to rats by tail vein injection. Then, urine was collected and the metformin concentration in urine was determined by HPLC. The localization and expression of rOCT2 in kidney were also investigated by Western blotting and immunohistochemistry. Significant differences of t 1/2, K e, CLtot and the accumulated metformin excretion in urine were founded in aged rats, but not in young rats, between metformin-treated group (2.002 ± 0.51 h, 0.346 ± 0.07/h, 57.161 ± 18.59 %, 4,287.087 ± 458.08 μg) and metformin plus atenolol-treated group (3.03 ± 0.67 h, 0.228 ± 0.05/h, 43.199 ± 10.28 %, 3,239.972 ± 446.61 μg). Moreover, a significant age-related decrease in rOCT2 protein expression was observed in the aged rats (P < 0.01), which may be responsible for the effect of atenolol on the renal excretion of metformin in the aged rats. In conclusion, there is a drug-drug interaction between atenolol and metformin, and more attention should be paid when atenolol and metformin were co-administered to the aged people inclinical.

Effects of Korean red ginseng extract on acute renal failure induced by gentamicin and pharmacokinetic changes by metformin in rats

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.

Protective effect and mechanism of metformin in rats with alcoholic liver disease

酒精性肝病(ALD)的发病与脂质代谢紊乱、肝细胞线粒体内脂肪酸氧化障碍和氧化应激等有关[1-2].腺苷酸活化蛋白激酶(AMPK)被称为细胞的"代谢感受器",存在于线粒体内,其信号通路是调节细胞能量状态的中心环节,AMPK激活后可以提高胰岛素敏感性、增加脂肪酸氧化及改善氧化应激.二甲双胍是AMPK的变构激活剂,可以通过调节AMPK、胰岛素受体(INSR)和固醇调节元件结合蛋白(SREBP)的表达来改善胰岛素抵抗,减轻酒精所致的肝脏损伤.本研究旨在探讨二甲双胍通过改善胰岛素抵抗而预防酒精性肝病的作用机制. 关键词：肝疾病,酒精性;大鼠;二甲双胍;预防和防护用药;胰岛素抗药性

Cardioprotective Effects of Metformin and Vildagliptin in Adult Rats with Insulin Resistance Induced by a High-Fat Diet

Insulin resistance has been shown to be associated with cardiac sympathovagal imbalance, myocardial dysfunction, and cardiac mitochondrial dysfunction. Whereas metformin is a widely used antidiabetic drug to improve insulin resistance, vildagliptin is a novel oral antidiabetic drug in a group of dipeptidyl peptidase-4 inhibitors in which its cardiac effect is unclear. This study aimed to determine the cardiovascular effects of metformin and vildagliptin in rats with insulin resistance induced by high-fat diet. Male Wistar rats were fed with either a normal diet or high-fat diet (n =24 each) for 12 wk. Rats in each group were divided into three subgroups to receive the vehicle, metformin (30 mg/kg, twice daily), or vildagliptin (3 mg/kg, once daily) for another 21 d. Heart rate variability (HRV), cardiac function, and cardiac mitochondrial function were determined and compared among these treatment groups. Rats exposed to a high-fat diet developed increased body weight, visceral fat, plasma insulin, cholesterol, oxidative stress, depressed HRV, and cardiac mitochondrial dysfunction. Metformin and vildagliptin did not alter body weight and plasma glucose levels but decreased the plasma insulin, total cholesterol, and oxidative stress levels. Although both metformin and vildagliptin attenuated the depressed HRV, cardiac dysfunction, and cardiac mitochondrial dysfunction, vildagliptin was more effective in this prevention. Furthermore, only vildagliptin prevented cardiac mitochondrial membrane depolarization caused by consumption of a high-fat diet. We concluded that vildagliptin is more effective in preventing cardiac sympathovagal imbalance and cardiac dysfunction, as well as cardiac mitochondrial dysfunction, than metformin in rats with insulin resistance induced by high-fat diet.

Pharmacokinetic and pharmacodynamic interaction between nifedipine and metformin in rats: competitive inhibition for metabolism of nifedipine and metformin by each other via CYP isozymes

It has been reported that hypertension exponentially increases in the patients with type 2 diabetes mellitus. Thus, this study was performed to investigate the pharmacokinetic and pharmacodynamic interactions between nifedipine and metformin, since both drugs were commonly metabolized via hepatic CYP2C and 3A subfamilies in rats.Nifedipine (3 mg/kg) and metformin (100 mg/kg) were simultaneously administered intravenously or orally to rats. Concentrations (I) of each drug in the liver and intestine, maximum velocity (Vmax), Michaelis–Menten constant (Km), and intrinsic clearance (CLint) for the disappearance of each drug, apparent inhibition constant (Ki) and [I]/Ki ratios of each drug in liver and intestine were determined. Also the metabolism of each drug in rat and human CYPs and blood pressure were also measured.After the simultaneous single intravenous administration of both drugs together, the AUCs of each drug were significantly greater than that in each drug alone due to the competitive inhibition for the metabolism of nifedipine by metformin via hepatic CYP3A1/2 and of metformin by nifedipine via hepatic CYP2C6 and 3A1/2. After the simultaneous single oral administration of both drugs, the significantly greater AUCs of each drug than that in each drug alone could have mainly been due to the competitive inhibition for the metabolism of nifedipine and metformin by each other via intestinal CYP3A1/2 in addition to competitive inhibition for the hepatic metabolism of each drug as same as the intravenous study.

Characterization of the Inhibitory Effects ofN-Butylpyridinium Chloride and Structurally Related Ionic Liquids on Organic Cation Transporters 1/2 and Human Toxic Extrusion Transporters 1/2-K In Vitro and In Vivo

Ionic liquids (ILs) are a class of salts that are expected to be used as a new source of solvents and for many other applications. Our previous studies revealed that selected ILs, structurally related organic cations, are eliminated exclusively in urine as the parent compound, partially mediated by renal transporters. This study investigated the inhibitory effects of N-butylpyridinium chloride (NBuPy-Cl) and structurally related ILs on organic cation transporters (OCTs) and multidrug and toxic extrusion transporters (MATEs) in vitro and in vivo. After Chinese hamster ovary cells expressing rat (r) OCT1, rOCT2, human (h) OCT2, hMATE1, or hMATE2-K were constructed, the ability of NBuPy-Cl, 1-methyl-3-butylimidazolium chloride (Bmim-Cl), N-butyl-N-methylpyrrolidinium chloride (BmPy-Cl), and alkyl substituted pyridinium ILs to inhibit these transporters was determined in vitro. NBuPy-Cl (0, 0.5, or 2 mg/kg per hour) was also infused into rats to assess its effect on the pharmacokinetics of metformin, a substrate of OCTs and MATEs. NBuPy-Cl, Bmim-Cl, and BmPy-Cl displayed strong inhibitory effects on these transporters (IC(50) = 0.2-8.5 μM). In addition, the inhibitory effects of alkyl-substituted pyridinium ILs on OCTs increased dramatically as the length of the alkyl chain increased. The IC(50) values were 0.1, 3.8, 14, and 671 μM (hexyl-, butyl-, and ethyl-pyridinium and pyridinium chloride) for rOCT2-mediated metformin transport. Similar structurally related inhibitory kinetics were also observed for rOCT1 and hOCT2. The in vivo coadministration study revealed that NBuPy-Cl reduced the renal clearance of metformin in rats. These results demonstrate that ILs compete with other substrates of OCTs and MATEs and could alter the in vivo pharmacokinetics of such substrates.

Pharmacokinetic interaction between itraconazole and metformin in rats: competitive inhibition of metabolism of each drug by each other via hepatic and intestinal CYP3A1/2

Fungal infection is prevalent in patients with diabetes mellitus. Thus, we investigated whether a pharmacokinetic interaction occurs between the anti-fungal agent itraconazole and the anti-glycaemic drug metformin, as both drugs are commonly administered together to diabetic patients and are metabolized via hepatic CYP3A subfamily in rats. Itraconazole (20 mg·kg(-1)) and metformin (100 mg·kg(-1)) were simultaneously administered i.v. and p.o. to rats. Concentrations (I) of each drug in the liver and intestine, maximum velocity (V(max)), Michaelis-Menten constant (K(m)) and intrinsic clearance (CL(int) ) for the disappearance of each drug, apparent inhibition constant (K(i) ) and [I]/K(i) ratios of each drug in the liver and intestine were determined. Also the metabolism of each drug in rat and human CYPs was measured in vitro. After simultaneous administration of both drugs, either i.v. or p.o., the total area under the plasma concentration-time curve from time zero to infinity (AUC)s of itraconazole and metformin were significantly greater than that of either drug administered alone. The metabolism of itraconazole and metformin was significantly inhibited by each other via CYP3A1 and 3A2 in rat and 3A4 in human microsomes. The significantly greater AUCs of itraconazole and metformin after i.v. administration of both drugs are probably due to competitive inhibition of the metabolism of each drug by each other via hepatic CYP3A1/2. Whereas after oral administration of both drugs, the significantly greater AUCs of each drug administered together than that of either drug alone is mainly due to competitive inhibition of intestinal metabolism of each drug by each other via intestinal CYP3A1/2.