Effects of High-Intensity Intermittent Training on Metabolic Parameters and Irisin Levels in High-Fat-Fed Rats

Objective:To investigate the effects of high-intensity intermittent training(HIIT)on preventing significant weight gain and provide scientific theoretical support and practical guidance for reducing the occurrence of obesity.Methods:Twenty-four Sprague-Dawley rats were randomly divided into four groups:the control sedentary group(CS),the high-fat sedentary group(HS),the high-fat continuous exercise group(HE),and the high-fat intermittent exercise group(HI).The HE and HI groups underwent five days of continuous low-intensity exercise and eight weeks of high-intensity intermittent exercise.Weekly monitoring included measurements of food intake and body weight.An automatic biochemical analyzer was used to assess blood lipid and glucose levels,while ELISA kits measured serum insulin and irisin content.H&E staining was used to observe adipocyte size.Results:In the HS group,body weight,blood lipid levels,blood glucose levels,and adipocyte size significantly increased,while the QUICKI index decreased.In the HI group,body weight,blood lipid levels,blood glucose levels,and adipocyte size decreased,and the QUICKI index increased.The effects of high-intensity intermittent exercise were superior to those of continuous low-intensity exercise.In the HI group,serum irisin levels did not change significantly after exercise,while in the HE group,there was a slight upward trend in irisin levels.Conclusion:A high-fat diet induced abnormal metabolism in rats.HIIT effectively prevents metabolic abnormalities induced by a high-fat diet,and its effects are more pronounced than those of low-intensity exercise.HIIT stimulates the secretion of blood irisin,affecting secretion levels,and may represent a novel mechanism for maintaining metabolic homeostasis.This has important implications for controlling significant weight gain.

Metabolic profile analysis of free amino acids in experimental autoimmune uveoretinitis rat plasma

AIM: To determine the differences of amino acid(AA) levels in experimental autoimmune uveoretinitis(EAU). METHODS: AA analysis of the plasma samples in EAU rats induced by interphotoreceptor retinoid-binding protein emulsion were performed with high performance liquid chromatography(HPLC) and phenylisothiocyanate(PITC) pre-column derivation methods were performed. Using partial least squares discriminant analysis(PLS-DA), the potential biomarkers were identified in EAU rat plasma, and the metabolic pathways related to EAU were further analyzed. RESULTS: The method results showed that linear(r≥0.9957), intra-day reproducible [relative standard deviation(RSD)=0.04%-1.33%], inter-day reproducible(RSD=0.06%-2.07%), repeatability(RSD=0.03%-0.89%), stability(RSD=0.05%-2.48%) and recovery(RSD=1.98%-4.39%), with detection limits of 0.853-11.4 ng/mL. The metabolic profile in EAU rats was different from that in the control groups five AAs concentrations were increased and nine AAs were reduced. Moreover, five metabolic pathways were related to the development of EAU. CONCLUSION: The developed method is a simple, rapid and convenient for determination of AAs in EAU rat plasma, and these findings will provide a comprehensiveinsight on the metabolic profiling of the pathological changes in EAU.

Apelin-12 improves metabolic and functional recovery of rat heart after global ischemia

This work was designed to explore efficacy of apelin-12 (A-12) as a cardioprotective agent when given before ischemia or at reperfusion using the isolated working heart model. Hearts of male Wistar rats were subjected to 30-min stabilization period followed by 35-min global ischemia and 30-min reperfusion. A short-term infusion of Krebs-Henseleit buffer (KHB) con-taining A-12 (35, 70, 140, 280 or 560 ?M) was ap-plied prior to ischemia (A-12-I) or at onset of reperfusion (A-12-R). KHB infusion was used as control. A-12 infusions induced a dose-dependent increase in recovery of coronary flow, contractile and pump function during reperfu-sion, with the largest augmentation of these indices in the A-12-I group. Both A-12 groups exhibited a significant reduction of LV diastolic pressure rise during reperfusion compared with control. Enhanced functional recovery in the A-12-I group was combined with a decrease in LDH leakage in perfusate on early reperfusion (by 36% vs. control, p < 0.05). Preischemic infusion of 140 ?M A-12 markedly increased myocardial ATP content, enhanced preservation of the total adenine nucleotide pool and improved recovery of the energy charge in reperfused hearts. There was a trend towards increase in myocardial phosphocreatine by the end of re- perfusion in the A-12-I group;however this benefit did not reach statistical significance. At the end of reperfusion, myocardial lactate and lactate/pyruvate ratio were on average 5-fold lower in A-12-I treated hearts compared with control ones and did not differ significantly from the initial values. Therefore, improved cardiac dysfunction after I/R injury and less cell mem-brane damage induced by A-12 are associated with maintaining high energy phosphates, particularly ATP, in reperfused myocardium. Changes in energy metabolism may play a role in mechanisms of cardioprotection afforded by A-12 during I/R stress.

Maternal low protein diet induces persistent expression changes in metabolic genes in male rats

BACKGROUND Perinatal exposure to a poor nutritional environment predisposes the progeny to the development of metabolic disease at the adult age,both in experimental models and humans.Numerous adaptive responses to maternal protein restriction have been reported in metabolic tissues.However,the expression of glucose/fatty acid metabolism-related genes in adipose tissue and liver needs to be described.AIM To evaluate the metabolic impact of perinatal malnutrition,we determined malnutrition-associated gene expression alterations in liver and adipose tissue.METHODS In the present study,we evaluated the alterations in gene expression of glycolytic/Krebs cycle genes(Pyruvate dehydrogenase kinase 4 and citrate synthase),adipogenic and lipolytic genes and leptin in the adipose tissue of offspring rats at 30 d and 90 d of age exposed to maternal isocaloric low protein(LP)diet throughout gestation and lactation.We also evaluated,in the livers of the same animals,the same set of genes as well as the gene expression of the transcription factors peroxisome proliferator-activated receptor gamma coactivator 1,forkhead box protein O1 and hepatocyte nuclear factor 4 and of gluconeogenic genes.RESULTS In the adipose tissue,we observed a transitory(i.e.,at 30 d)downregulation of pyruvate dehydrogenase kinase 4,citrate synthase and carnitine palmitoyl transferase 1b gene expression.Such transcriptional changes did not persist in adult LP rats(90 d),but we observed a tendency towards a decreased gene expression of leptin(P=0.052).The liver featured some gene expression alterations comparable to the adipose tissue,such as pyruvate dehydrogenase kinase 4 downregulation at 30 d and displayed other tissue-specific changes,including citrate synthase and fatty acid synthase upregulation,but pyruvate kinase downregulation at 30 d in the LP group and carnitine palmitoyl transferase 1b downregulation at 90 d.These gene alterations,together with previously described changes in gene expression in skeletal muscle,may account for the metabolic adaptations in response to maternal LP diet and highlight the occurrence of persistent transcriptional defects in key metabolic genes that may contribute to the development of metabolic alterations during the adult life as a consequence of perinatal malnutrition.CONCLUSION We conclude that perinatal malnutrition relays long-lasting transcriptional alterations in metabolically active organs,i.e.,liver and adipose tissue.

Effects of Maternal Linseed Oil Supplementation on Metabolic Parameters in Cafeteria Diet-induced Obese Rats

Because linseed oil may influence maternal and fetal metabolisms, we investigated its role in the modulation of lipid metabolism in cafeteria diet-induced obese rats and their offspring. Female Wistar rats were fed control or cafeteria food, which were either supplemented or not supplemented with linseed oil （5%） for I month before and during gestation. At parturition, serum and tissue lipids and enzyme activities were analyzed. Cafeteria diet induced adverse metabolic alterations in both mothers and offspring. Linseed oil improved metabolic status. In conclusion, linseed oil displayed health benefits by modulating tissue enzyme activities in both obese mothers and their newborns.

Age-related Metabolic Effects of Acetaldehyde on Rats With Reference to Detoxification Enzymes and Sulfhydryl Groups

Induced-acetaldehyde toxic effects on gluatathione [GSH] metabolism and sulfhydryl (SH) groups in liver and in brain of female albino rats with reference to age was studied.The total -SH groups were decreased whereas the specific activities of glutathione-S-transferase [GST] and glutathione peroxidase [GP0] were increased in acetaldehyde treated rats. However, the specific activity levels of glutathione reductase [GR] and Γ-glutamylcysteine synthetase [Γ-GCS] were decreased. In general, acetaldehyde indueed changes in the specific activities of the enzymes that increase with increasing age

Effect of the modified wendan decoction on hippocampal astrocyte neurotrophy by regulating the TRP-KYN metabolic pathway in depression-model rats

Objective:To observe the effect of the modified Wendan decoction on the neurotrophic function of hippocampal astrocytes by regulating the tryptophan-kynurenine(TRP-KYN)neuroprotective metabolic pathway in depression-model rats.Methods:A total of 96 Sprague Dawley(SD)rats were randomly divided into the blank group,model group,sham surgery group,neurotoxicity blocker group(blocker 1 for short)group,decoction group,fluoxetine group,blocker 1 plus decoction group,and blocker 1 plus fluoxetine group.Depression in rats of all groups,except for the blank group,was generated by isolation combined with chronic unpredictable mild stress.After corresponding treatments of the rats in each group,the sucrose preference test was performed to evaluate the depressive behaviors of the rats.Serum levels of tryptophan(TRP),kynurenine(KYN),and kynurenic acid(KYNA)were detected via enzyme-linked immunosorbent assay(ELISA);the mRNA/protein expression of hippocampal astrocyte markers,glial fibrillary acidic protein(GFAP)and S100β,was detected via reverse transcription-polymerase chain reaction(RT-PCR)and immunohistochemistry.ELISA and RT-PCR were carried out to detect the levels/mRNA expressions of brain-derived neurotrophic factor(BDNF)and glial-cell-line-derived neurotrophic factor(GDNF),the nutrient secretions of hippocampal astrocytes in rats.Results:Compared to the blank group,the number of activities of rats was significantly reduced,and the GFAP expression in the hippocampus was significantly increased while the BDNF and GDNF expressions were significantly decreased in the model group.With the intervention of the modified Wendan decoction,the depression of rats was significantly improved,and the BDNF and GDNF expressions in the hippocampus were increased while the GFAP expression was decreased significantly in the model group.Conclusion:The modified Wendan decoction may improve the neurotrophic function of rats’hippocampal astrocytes by enhancing the neuroprotective function of the TRP-KYN pathway,thereby exerting an antidepressant effect.

Identification of the metabolite and cytochrome P450 isoforms involved in rat liver microsomal metabolism of TM208

To identify the metabolite and CYP450 isoforms involved in rat liver microsomal metabolism of TM208. The present study investigated the metabolism of TM208 and the effects of selective CYP450 inhibitors on the metabolism of TM208 in rat liver microsomes. Various specific inhibitors of CYP were used to identify the isoforms of CYP involved in the metabolism of TM208. The inhibitor of CYP2D and that of CYP2B had strong inhibitory effects on TM208 metabolism in a concentration-de- pendant manner, the inhibitor of CYP1A had a modest inhibitory effect, and the inhibitor of CYP3A seemed not to have an obvious inhibitory effect on TM208 metabolism. TM208 might mainly be metabolized by CYP2D and CYP2B in rat liver microsomes.

MicroRNA expression profile and lipid metabolism characteristics in liver of rat undergoing high-fat diet

This study aimed to investigate the microRNA expression profile and the characteristics of lipid metabolism in the livers of rats undergoing a high-fat diet.Fifty male Sprague-Dawley(SD)rats were divided into a standard chow group(C group,N=10)and a high-fat diet group(H group,N=40).After 12 weeks,the rat body weight,body length,fat mass,and serum lipid concentration were measured.The expression profile of microRNAs and the gene and protein expression levels involved in lipid metabolism in rat liver were detected.Body fat and serum lipid concentrations were all significantly higher in the H group than those in the C group(p<0.05 or p<0.01).The expression of 10 microRNAs showed significant differences in the liver(p<0.05).In particular,the let-7 family expression levels significantly increased(p<0.05)in the H group compared with those in the C group.Compared with the C group,the high-fat diet resulted in low FAS,CPT1A,and ApoAI mRNA expression levels(p<0.05 or p<0.01)and high PPARαand FAT/CD36 mRNA expression levels in the H group rat liver(p<0.01).Meanwhile,the protein PPARα,FAS,CPT1A,FAT/CD36,and ApoAI expression levels were all significantly lower in the H group than those in the C group(p<0.05 or p<0.01).In conclusion,the high-fat diet increased the body fat and serum lipid levels and altered the 10 microRNA expression levels in the liver.The high-fat diet may affect hepatic carbohydrate metabolism and increase ectopic fat accumulation through let-7 family overexpression.The high-fat diet for 12 weeks decreased lipid metabolism level in the liver,thereby decreasing fatty acid synthesis,oxidation,and transport by down-regulating the PPARα,FAS,CPT1A,FAT/CD36,and ApoAI protein levels.

Metabolism of Mequindox in Isolated Rat Liver Cells

Mequindox （MEQ）, 3-methyl-2-quinoxalinacetyl-l,4-dioxide, is widely used in Chinese veterinary medicine as an antimicrobial agent and feed additive. Its toxicity has been reported to be closely related to its metabolism. To understand the pathways underlying MEQ＇s metabolism more clearly, we studied its metabolism in isolated rat liver cells by using liquid chromatography coupled with electrospray ionization hybrid linear trap quadrupole orbitrap （LC-LTQ-Orbitrap） mass spectrometry. The structures of MEQ metabolites and their product ions were readily and reliably characterized on the basis of accurate MS2 spectra and known structure of MEQ. Eleven metabolites were detected in isolated rat liver cells, two of which were detected for the first time in vitro. The major metabolic pathways reported previously for in vitro metabolism of MEQ in rat microsomes were confirmed in this study, including N O group reduction, carbonyl reduction, and methyl monohydroxylation. In addition, we fotmd that acetyl hydroxylation was an important pathway of MEQ metabolism. The results also demonstrate that cellular systems more closely simulate in vivo conditions than do other in vitro systems such as microsomes. Taken together, these data contribute to our understanding of the in vivo metabolism of MEQ.

Effect of Different Calcium Supplements on Bone Metabolism in Rats

Osteoporosis, characterized by loss of bone mass and microarchitectural deterioration of bone tissue, results in enhanced bone fragility and increases risk of fractureIll. In China, the incidence of primary osteoporosis is as high as 50%-70% in 60-69 years old females and approximately 30% in 60-69 years old males[21, which is closely related with the low intake of calcium. According to the nationwide nutrition and health survey in 2002 in China, the average daily calcium intake of Chinese residents is 391 mg, accounting for 41% of the recommended calcium intake.

Effect of Starvation-Refeeding Status on Cholesterol Metabolism in Rats Fed High-Cholesterol Diet

The present study investigated the effect of starvation-refeeding status on cholesterol metabolism in rats fed a high-cholesterol diet or a cholesterol-free diet. Twenty male and 20 female Donryu rats (age 5 weeks) were fed a cho-lesterol-free diet for 14 days. Then the male and female rats were each divided into two groups: feeding and starva-tion-refeeding groups. The feeding groups were fed the experimental diet for 3 days, and the starvation-refeeding groups fasted for 2 days followed by 3 days of feeding. Half of each of groups was fed a cholesterol-free diet and the other half was fed a high-cholesterol diet. Starvation-refeeding significantly increased the plasma free cholesterol and HDL-cholesterol concentrations in both the high-cholesterol-diet-fed rats and the cholesterol-free-diet-fed rats. In the female rats, plasma total cholesterol and cholesteryl ester concentrations were significantly higher in the high-cholesterol groups than in the cholesterol-free groups, whereas TG concentration and total cholesterol/TG ratio were not significantly different among all of the groups. Liver total cholesterol and cholesteryl ester were significantly higher in the high-cholesterol groups than in the cholesterol-free groups in both male and female rats. These results suggest that starvation-refeeding affected cholesterol metabolism at least in part. The reactivity of the cholesterol me-tabolism may be different between male and female rats.

Chiral metabolism of propafenone in rat hepatic microsomes treated with two inducers

AIM: To study the influence of inducers of drug metabolism enzyme, beta-naphthoflavone (BNF) and dexamethasone (DEX), on the stereoselective metabolism of propafenone in the rat hepatic microsomes. METHODS: Phase I metabolism of propafenone was studied using the microsomes induced by BNF and DEX and the non-induced microsome was used as the control. The enzymatic kinetics parameters of propafenone enantiomers were calculated by regress analysis of Eadie-Hofstee Plots. Propafenone enantiomer concentrations were assayed by a chiral HPLC. RESULTS: The metabolite of propafenone, N-desalkylpropafenone, was found after incubation of propafenone with the rat hepatic microsomes induced by BNF and DEX. In these two groups, the stereoselectivity favoring R(-) isomer was observed in metabolism at low substrate concentrations of racemic propafenone, but lost the stereoselectivity at high substrate concentrations. However, in control group, no stereoselectivity was observed. The enzyme kinetic parameters were: (1) K(m). Control group: R(-) 83+/-6, S(+) 94+/-7; BNF group: R(-) 105+/-6, S(+)128+/-14; DEX group: R(-) 86+/-11, S(+) 118+/-16; (2)V(max). Control group: R(-) 0.75+/-0.16, S(+) 0.72+/-0.07; BNF group: R(-) 1.04+/-0.15, S(+)1.07+/-14; DEX group: R(-) 0.93+/-0.06, S(+) 1.04+/-0.09; (3)Cl(int). Control group: R(-) 8.9+/-1.1, S(+) 7.6+/-0.7; BNF group: R(-) 9.9+/-0.9, S(+)8.3+/-0.7; DEX group: R(-) 10.9+/-0.8, S(+) 8.9+/-0.9. The enantiomeric differences in K(m) and Cl(int) were both significant, but not in V(max), in BNF and DEX group. Whereas enantiomeric differences in three parameters were all insignificant in control group. Furthermore, K(m) and V(max) were both significantly less than those in BNF or DEX group. In the rat liver microsome induced by DEX, nimodipine (NDP) decreased the stereoselectivity in propafenone metabolism at low substrate concentration. The inhibition of NDP on the metabolism of propafenone was stereoselective with R(-)-isomer being impaired more than S(+)-isomer. The inhibition constant (Ki) of S(+)- and R(-)-propafenone, calculated from Dixon plots, was 15.4 and 8.6 mg x L(-1), respectively. CONCLUSION: CYP1A subfamily(induced by BNF) and CYP3A4 (induced by DEX) have pronounced contribution to propafenone N-desalkylation which exhibited stereoselectivity depending on substrate concentration. The molecular base for this phenomenon is the stereoselectivity in affinity of substrate to the enzyme activity centers instead of at the catalyzing sites.

A Validated Liquid Chromatography-Mass Spectrometry Method for the Detection and Quantification of Oxidative Metabolites of 2,2',4,4'-Tetrabromodiphenyl Ether in Rat Hepatic Microsomes

In the present study, we developed and validated an analytical method using ultra performance liquid chromatography-mass spectrometry (UPLC/MS) for the quantitative determination of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) metabolism by rat hepatic microsomes. BDE-47 is a brominated flame retardant that was widely used in a variety of consumer products and has subsequently been identified as a ubiquitous environmental contaminant. Hydroxy-bromodiphenyl ethers (OH-BDEs) were isolated from rat hepatic microsomes by liquid-liquid extraction. Chromatographic separation was achieved by UPLC on a C18 column with gradient elution using a mobile phase consisting of methanol and water, each containing 0.1% formic acid, at a flow rate of 0.2 mL/min. Detection and quantification were performed using a mass spectrometer in single ion recording mode with negative electrospray ionization. The UPLC/MS method was validated for linearity, limit of quantification (LOQ), accuracy, precision and recovery. The weighted calibration curves (1/X2) were linear over a concentration range of 5 - 250 nM with LOQ values between 5 nM and 50 nM for the individual OH-BDEs. Intra- and inter- day accuracy (%DEV) and precision (%RSD) values ranged from –11.7% to 9.5% and 5.9% to 16.5%, respectively. Recovery values of 70% to 90% were obtained for all OH-BDEs. The validated method allowed us to successfully analyze metabolite formation following incubation of BDE-47 with hepatic microsomes prepared from phenobarbital-treated rats. Results demonstrate that the UPLC/MS method has sufficient sensitivity and reproducibility to fully characterize the in vitro metabolism of BDE-47 and possibly other PBDEs.

Oxidative Metabolism of Estrone Modified by Genistein and Bisphenol A in Rat Liver Microsomes

Genistein, the main isoflavone from soy, and bisphenol A （BPA）, a food contaminant, are considered ubiquitous xenoestrogens. Here we investigated the influence of genistein and BPA on estrone （El） metabolism in rat liver microsomes. Both substances inhibited the 2-hydroxylation and 16a-hydroxylation of E1, but in different degrees, thereby reducing the 2-OH-E1/16a-OH-E1 ratio,

In situ absorption and metabolism of stilbene glycoside in rat

Stilbene glycoside(TSG)has been shown to have many beneficial properties.It is therefore essential to understand the absorption and metabolism of TSG in detail.We determined the recovery of TSG and its metabolites(TSG sulfate/glucuronides)in rat gastric contents,gastric mucosa,portal vein plasma,celiac arterial plasma,bile,and urine after administration of 15 mg of TSG in 0.5 mL physiological saline or incubation for 20 min in situ in the stomach of rats.Within 20 min,(64.0±9.8)% of the administered TSG disappeared from the stomach;later,TSG was recovered in both free and conjugated forms in plasma and bile,but not in urine.On the other hand,only free TSG was detected in the gastric contents and mucosa;it was also detected in the portal vein plasma as(48.1±3.5)% of the total TSG(all forms of TSG).However,the proportion of free TSG in the celiac arterial plasma and bile decreased to 4%-10%.In addition,the proportion of free TSG to total TSG in the liver microsome incubation mixture after TSG was incubated in liver microsome at 37 ℃ for 30 min was very low [(10.6 ± 2.6)%].These results indicate that TSG could be quickly absorbed from the rat stomach,conjugated in liver and excreted in bile.Such novel information would be helpful for the use of TSG as a beneficial natural product which may improve its proposed efficacy in preventing chronic diseases.

Changes of Liver Microsomal Drug-metabolizing System and Lipoperoxidation Activity in Scalded Rats and the Effects of Silybin

The dynamic changes of liver microsomal drug-metabolizing system (MDMS) andlipoperoxidation were studied in scalded rats. The effects of treatment with vitamin E and silybinwere also evaluated. The results showeed that liver microsomal cytochrome P-450 content, and p-nitroanisole demethylase (P-NOD) and aniline hydroxylase (AH) activity decreased markedlypostburn. On the contrary, liver lipoperoxide and mierosomal lipoperoxidation increased significantlyafter scalding. Both the increase of liver lipoperoxide and mierosomal lipoperoxidation and the de-crease of MDMS activity were prevented by vitamin E and silybin treatments.

Changes of Selenium Metabolism Glutathione Peroxidase Activity and Lipid Peroxides Content in Severely Scalding-injured Rats

The changes of sclenium metabolism, glutathione peroxidase activity and lipid peroxidescontent in the tissues of rats suffering from 30% TBSA full thickness scalding were observed in thefirst 7 days after injury. It was found that selenium content in the rat tissues decreased remarkably af-ter injury, which in turn resulted in serious reduction of glutathione peroxidasc activity and significantincrease of lipid peroxides in the scrum, crythrocytcs and liver. However the muscular tissue showedno significant changes. These facts imply that after burn injury, the body is in a state of selenium deficiency, the lossof selenium might be responsible for the reduction of anti - peroxidation ability of glutathioneperoxidase, and conscqucntly there is an increase of lipid peroxides in the tissues. Only the musculartissue is insensitive to lipid peroxidation. It is believed that the reduction of anti-peroxidation abilityof glutathione peroxidasc after bum injury might be one of the main causes to intensify, the injury re-suiting from free radicals.

Effect of vitamin A and E on carbohydrate and lipid metabolism in diet-induced obese wistar rats

In the present study, we investigated the biochemical alterations and gene expression of carbohydrate and lipid metabolism after oral administration of vitamin A and E for 2 months in diet-induced obese Wistar rats. Vitamin A and E administration reduced significantly the increase in body weight and food intake and normalized the alterations in lipid profiles in obese rats compared to normal rats. Moreover, both vitamins decreased the fat accumulation in liver tissues of obese rats. Finally, they up-regulated mRNA expression of Pyruvate Kinase (PK) and Glucose Transporter-2 (GLUT-2), and increased lipolysis and cholesterol metabolism through up-regulation of lipoprotein lipase (LPL), Sterol Responsible Element Binding Protein-1a (STREBP-1a) and STREBP-1c mRNA expression. In conclusion, vitamin A and E regulate gene expression of carbohydrate and lipid metabolism, and also ameliorate changes associated with obesity induced by high fat diet in Wistar rats.

<i>In Vitro</i>Competitive Metabolism Study of Olmesartan Medoxomil in Rat Liver S9 Fractions Using LC/MS

Olmesartan Medoxomil (OLM), Ramipril (RPL) & Fenofibric acid (FA) are used to treat hypertension and cardiovascular disease. These drugs undergo hydrolytic metabolism by the enzyme liver esterase and converts into their respective active metabolites Olmesartan (OL), Ramiprilat (RPT) and Fenofibric acid (FA) for OLM, RPL and FEN respectively. In this study the competitive metabolism of OLM, in presence of RPL and FEN was investigated in rat liver s9 fractions using a validated LC-MS method. Olmesartan Medoxomil was found to be highly reactive to the rat liver S9 fractions and formation of active metabolite Olmesartan is highest. The rate of formation of active metabolite Olmesartan reduced by 12.68% in the presence Ramipril and 6.56% in presence of Fenofibrate. A marked reduction of 18.96% was found in the formation of active metabolite Olmesartan from Olmesartan Medoxomil when all the three drugs are in combination.