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PubMed2005

PPAR-alpha expression inversely correlates with inflammatory cytokines IL-1beta and TNF-alpha in aging rats.

Dehydroepiandrosterone (DHEAS) was given the name "fountain of youth" in reference to its beneficial properties in memory, cognition and aging. Cultured cell studies showed that DHEAS may mediate its action by counteracting aging-associated inflammation via PPAR-alpha activation. In the present study, we demonstrated an age-dependent increase in IL-1beta and TNF-alpha expression in the brain and the spleen of aging rats, while PPAR-alpha expression was decreased in the spleen of 18 month-old rats. Oral treatment with DHEAS increased PPAR-alpha mRNA in 3 month-old rats and decreased PPAR-alpha protein expression in 18 month-old rats in the spleen. In contrast, DHEAS did not alter cytokine expression in spleen and brain of the three age groups. These findings underline a differential role for DHEAS in PPAR-alpha expression that is age-dependent, and also, that beneficial effects of DHEAS on cognitive function are unlikely mediated by a decrease in cytokine expression.

Aging↗
PubMed2002

PPAR-alpha ligands inhibit H2O2-mediated activation of transforming growth factor-beta1 in human mesangial cells.

Transforming growth factor-beta1 (TGF-beta1) mediates the development of glomerulosclerosis by stimulating mesangial cell production of extracellular matrix (ECM) proteins. TGF-beta1 and several ECM genes are regulated by promoter O-tetradecanoylphorbol 13-acetate-responsive elements (TREs) that are transactivated by the activator protein-1 (AP-1) transcription factor complex. AP-1-TRE interactions are regulated by redox changes. Recently, peroxisome proliferator-activated receptors (PPARs) were shown to negatively regulate several transcription factor families. In these studies, we postulated that PPAR-alpha could antagonize TGF-beta1 expression by cultured human mesangial cells (HMC). A TGF-beta1 luciferase expression plasmid was transduced into HMC via recombinant deficient adenoviral vectors. The TGF-beta1 promoter activity increased twofold (209%) following 18-h treatments with H(2)O(2) (1,000 micro M). Using RT-PCR, we demonstrated that HMC possess PPAR-alpha RNA, and PPAR-alpha protein was identified by immunohistochemistry. Pretreatment of cells with the PPAR-alpha ligands WY14643 (100-500 micro M) or clofibrate (100-500 micro M) dose-dependently inhibited oxidant-mediated induction of TGF-beta1. This inhibition occurred without affecting the H(2)O(2)-mediated activation of the mitogen-activated protein kinase (MAPK) pathways extracellular regulated kinase, p38 MAPK, or Jun N-terminal kinase, which are responsible for the regulation of AP-1 phosphorylation. These studies are the first to identify PPAR-alpha expression by HMC. The results of these studies suggest that TGF-beta1 expression mediated by oxidant stress may be suppressible by PPAR-alpha activation.

Cells, Cultured↗
PubMed1997

PPAR alpha mediates peroxisome proliferator-induced transcriptional repression of nonperoxisomal gene expression in mouse.

The strain difference, peroxisome proliferator specificity and role of PPAR alpha in peroxisome proliferator-induced transcriptional repression of nonperoxisomal transthyretin and alpha2u-globulin genes were examined. The genes were repressed by four peroxisome proliferators in all seven mouse strains tested. The extent of repression was strongly dependent on both the mouse strains and type of proliferator, although the mRNA levels of PPAR alpha and its partner in heterodimerization, RXR alpha were not different. The role of PPAR alpha in repression was confirmed by the finding that PPAR alpha-null mice were not responsive to transcriptional repression. These results indicate that PPAR alpha plays an obligatory role in transcription of various genes, some of which are not related to lipid metabolism.

Alpha-Globulins↗
PubMed2006

Inhibition of PPAR-alpha activity in mice with cardiac-restricted expression of tumor necrosis factor: potential role of TGF-beta/Smad3.

A shift in energy substrate utilization from fatty acids to glucose has been reported in failing hearts, resulting in improved oxygen efficiency yet perhaps also contributing to a state of energy deficiency. Peroxisome proliferator-activated receptor (PPAR)-alpha, the principal transcriptional regulator of cardiac fatty acid beta-oxidation (FAO) genes, is downregulated in heart failure, and this may contribute to reduced fatty acid utilization. Cardiomyopathic states are also accompanied by elevated levels of circulating cytokines, such as tumor necrosis factor (TNF), as well as increased local production of cytokines and profibrotic factors, such as transforming growth factor (TGF)-beta. However, whether these molecular pathways directly modulate cardiac energy metabolism and PPAR-alpha activity is not known. Therefore, FAO capacity and FAO gene expression were determined in mice with cardiac-restricted overexpression of TNF (MHCsTNF(3)). MHCsTNF(3) hearts had significantly lower FAO capacity and decreased expression of PPAR-alpha and FAO target genes compared with control hearts. Surprisingly, TNF had little effect on PPAR-alpha activity and FAO rates in cultured ventricular myocytes, suggesting that TNF acts indirectly on myocyte FAO in vivo. We found that TGF-beta expression was upregulated in MHCsTNF(3) hearts and that treatment of cultured myocytes with TGF-beta significantly suppressed FAO rates and directly impaired PPAR-alpha activity, a result reproduced by Smad3 overexpression. This work demonstrates that TGF-beta signaling pathways directly suppress PPAR-alpha activity and reduce FAO in cardiac myocytes, perhaps in response to locally elevated TNF. Although speculative, TGF-beta-driven repair mechanisms may also include the additional benefit of limiting FAO in injured myocardium.

Animals↗
PubMed2006

The effects of Musk T on peroxisome proliferator-activated receptor [PPAR]-alpha activation, epidermal skin homeostasis and dermal hyaluronic acid synthesis.

Peroxisome proliferators activated receptors (PPARs) are a family of nuclear hormone receptors that heterodimer with the retinoid X receptor and function as transcriptional regulators of genes. Topically Applied PPAR-alpha agonists possess receptor mediated, pro-differentiating/anti-proliferative effects, lipid metabolism stimulation, and anti-inflammatory activity, which suggest that they could be beneficial for the treatment of a variety of cutaneous diseases. Hyaluronan (HA), a high-molecular-weight linear glycosaminoglycan consisting of alternating D: -glucuronic acid and N-acetyl-D: -glucosamine residues, is one of the major extracellular matrix components in skin. Among the family of HA synthase genes (HAS1, 2, 3) so far identified, one group has demonstrated that the expressions of HAS2 and HAS3 play crucial roles in the regulation of HA synthesis in human skin fibroblasts and keratinocytes, respectively, but the precise regulatory mechanisms are still unknown. We examine Musk T called Ethylene brassylate, Astratone or 1,4-Dioxacycloheptadecane-5,17-dione, which used as just a perfume ingredient, plays a role as PPAR-alpha ligand in vitro and stimulates skin barrier recovery, ceramide synthesis, beta-Glucocerebrosidase, involucrin expression in epidermis in vivo; and examine that Musk T stimulates HAS expression and HA synthesis in human skin fibroblast. Through these experiments, we conclude that Musk T is PPAR-alpha ligand, effects on keratinocyte differentiation, intercellular lipid synthesis in epidermis, HA synthesis stimulation in dermis.

Animals↗
PubMed2006

Influence of PPAR-alpha agonist fenofibrate on insulin sensitivity and selected adipose tissue-derived hormones in obese women with type 2 diabetes.

PPAR-alpha agonists improve insulin sensitivity in rodent models of obesity/insulin resistance, but their effects on insulin sensitivity in humans are less clear. We measured insulin sensitivity by hyperinsulinemic-isoglycemic clamp in 10 obese females with type 2 diabetes before and after three months of treatment with PPAR-alpha agonist fenofibrate and studied the possible role of the changes in endocrine function of adipose tissue in the metabolic effects of fenofibrate. At baseline, body mass index, serum glucose, triglycerides, glycated hemoglobin and atherogenic index were significantly elevated in obese women with type 2 diabetes, while serum HDL cholesterol and adiponectin concentrations were significantly lower than in the control group (n=10). No differences were found in serum resistin levels between obese and control group. Fenofibrate treatment decreased serum triglyceride concentrations, while both blood glucose and glycated hemoglobin increased after three months of fenofibrate administration. Serum adiponectin or resistin concentrations were not significantly affected by fenofibrate treatment. All parameters of insulin sensitivity as measured by hyperinsulinemic-isoglycemic clamp were significantly lower in an obese diabetic group compared to the control group before treatment and were not affected by fenofibrate administration. We conclude that administration of PPAR-alpha agonist fenofibrate for three months did not significantly affect insulin sensitivity or resistin and adiponectin concentrations in obese subjects with type 2 diabetes mellitus. The lack of insulin-sensitizing effects of fenofibrate in humans relative to rodents could be due to a generally lower PPAR-alpha expression in human liver and muscle.

Adipokines↗
PubMed2005

PPAR-alpha activators suppress STAT1 inflammatory signaling in lipopolysaccharide-activated rat glia.

Signal transducers and activators of transcription (STATs) have recently been reported to mediate glial activation, and thus potentially play important roles in many neuroinflammatory diseases. We examined the effect of peroxisome proliferator-activated receptor (PPAR) activators on inflammatory responses in cultured rat brain glial cells. Four PPAR-alpha activators were tested, three fibrates (WY14643, clofibrate and fenofibrate) and an arachidonic acid derivative (5,8,11,14-eicosatetraynoic acid). We found that all four PPAR-alpha activators suppressed lipopolysaccharide-stimulated STAT1 phosphorylation and nuclear factor binding to gamma-interferon-activated sequence/interferon-alpha-stimulated response element sites known to contain STAT binding sites. PPAR-alpha activators also suppressed lipopolysaccharide-stimulated tumor necrosis factor-alpha and monocyte chemoattractant protein-1 transcription and release. These results suggest that PPAR-alpha activators may be useful in the treatment of inflammatory brain diseases.

Animals↗
PubMed2005

Salacia oblonga root improves cardiac lipid metabolism in Zucker diabetic fatty rats: modulation of cardiac PPAR-alpha-mediated transcription of fatty acid metabolic genes.

Excess cardiac triglyceride accumulation in diabetes and obesity induces lipotoxicity, which predisposes the myocytes to death. On the other hand, increased cardiac fatty acid (FA) oxidation plays a role in the development of myocardial dysfunction in diabetes. PPAR-alpha plays an important role in maintaining homeostasis of lipid metabolism. We have previously demonstrated that the extract from Salacia oblonga root (SOE), an Ayurvedic anti-diabetic and anti-obesity medicine, improves hyperlipidemia in Zucker diabetic fatty (ZDF) rats (a genetic model of type 2 diabetes and obesity) and possesses PPAR-alpha activating properties. Here we demonstrate that chronic oral administration of SOE reduces cardiac triglyceride and FA contents and decreases the Oil red O-stained area in the myocardium of ZDF rats, which parallels the effects on plasma triglyceride and FA levels. Furthermore, the treatment suppressed cardiac overexpression of both FA transporter protein-1 mRNA and protein in ZDF rats, suggesting inhibition of increased cardiac FA uptake as the basis for decreased cardiac FA levels. Additionally, the treatment also inhibited overexpression in ZDF rat heart of PPAR-alpha mRNA and protein and carnitine palmitoyltransferase-1, acyl-CoA oxidase and 5'-AMP-activated protein kinase mRNAs and restored the downregulated acetyl-CoA carboxylase mRNA. These results suggest that SOE inhibits cardiac FA oxidation in ZDF rats. Thus, our findings suggest that improvement by SOE of excess cardiac lipid accumulation and increased cardiac FA oxidation in diabetes and obesity occurs by reduction of cardiac FA uptake, thereby modulating cardiac PPAR-alpha-mediated FA metabolic gene transcription.

Animals↗
PubMed2005

The dependence of serum interleukin-6 level on PPAR-alpha polymorphism in men with coronary atherosclerosis.

BACKGROUND: The association between L162V polymorphism in the gene for peroxisome proliferator activated receptor (PPAR) alpha and the development of coronary heart disease was examined. METHODS: PPAR-alpha polymorphism was determined in 48 men with angiographically confirmed coronary atherosclerosis and in 51 healthy men. RESULTS: The frequency of the V allele of the L162V polymorphism was four times higher in men with atherosclerosis (0.25 in studied group and 0.06 in controls). The polymorphism was not associated with changes in body mass index, lipid pattern, serum adhesion molecules, or vasoactive agents concentrations. The effect of the polymorphism on the serum interleukin-6 level (IL-6) was observed (p<0.01). The serum IL-6 level was higher in homozygotic than in heterozygotic subjects (p<0.02). Multivariate regression analysis showed the existence of a relationship between simvastatin therapy and serum IL-6 level (r=0.83; p<0.05) in the homozygotic men. While in homozygotic patients with atherosclerosis a negative linear correlation between serum IL-6 and NO concentration was shown, in heterozygotic men positive correlations between IL-6 or HDL cholesterol and adhesion molecule levels were found. CONCLUSION: L162V polymorphism in the gene for PPAR-alpha seems to be associated with atherosclerosis through a mechanism including regulation of the IL-6 level.

Journal Article↗
PubMed2006

Gypenoside XLIX, a naturally occurring gynosaponin, PPAR-alpha dependently inhibits LPS-induced tissue factor expression and activity in human THP-1 monocytic cells.

Tissue factor (TF) is involved not only in the progression of atherosclerosis and other cardiovascular diseases, but is also associated with tumor growth, metastasis, and angiogenesis and hence may be an attractive target for directed cancer therapeutics. Gynostemma pentaphyllum (GP) is widely used in the treatment of various cardiovascular diseases including atherosclerosis, as well as cancers. Gypenoside (Gyp) XLIX, a dammarane-type glycoside, is one of the prominent components in GP. We have recently reported Gyp XLIX to be a potent peroxisome proliferator-activated receptor (PPAR)-alpha activator. Here we demonstrate that Gyp XLIX (0-300 microM) concentration dependently inhibited TF promoter activity after induction by the inflammatory stimulus lipopolysaccharide (LPS) in human monocytic THP-1 cells transfected with promoter reporter constructs pTF-LUC. Furthermore, Gyp XLIX inhibited LPS-induced TF mRNA and protein overexpression in THP-1 monocyte cells. Its inhibition of LPS-induced TF hyperactivity was further confirmed by chromogenic enzyme activity assay. The activities of Gyp XLIX reported in this study were similar to those of Wy-14643, a potent synthetic PPAR-alpha activator. Furthermore, the Gyp XLIX-induced inhibitory effect on TF luciferase activity was completely abolished in the presence of the PPAR-alpha selective antagonist MK-886. The present findings suggest that Gyp XLIX inhibits LPS-induced TF overexpression and enhancement of its activity in human THP-1 monocytic cells via PPAR-alpha-dependent pathways. The data provide new insights into the basis of the use of the traditional Chinese herbal medicine G. pentaphyllum for the treatment of cardiovascular and inflammatory diseases, as well as cancers.

Anti-Inflammatory Agents↗
PubMed2006

In vitro and in vivo effects of the PPAR-alpha agonists fenofibrate and retinoic acid in endometrial cancer.

UNLABELLED: Fenofibrate, an agonist of PPAR-alpha, in doses above 25 microM, inhibits proliferation and induces apoptosis in Ishikawa endometrial cancer cells. We show that these effects are potentiated by retinoic acid, an agonist of the retinoid-X-receptor. DNA content analysis shows that G1/S phase progression through the cell cycle is inhibited. Independent Component Analysis of gene microarray experiments demonstrated downregulation of Cyclin D1 (CCND1) and associated changes in cell cycle gene expression. Expression of PPAR-alpha mRNA was reduced by >75% using RNA-interference but this resulted in only minor changes in biological effects. A nude mouse model of endometrial carcinoma was used to investigate the effect of fenofibrate in vivo but failed to show consistent inhibition of tumour growth. CONCLUSION: The combination of fenofibrate and retinoic acid is a potent inhibitor of Ishikawa endometrial cancer cell growth in vitro.

Animals↗
PubMed2005

A dominant negative human peroxisome proliferator-activated receptor (PPAR){alpha} is a constitutive transcriptional corepressor and inhibits signaling through all PPAR isoforms.

Several missense mutations in the ligand-binding domain of human peroxisome proliferator-activated receptor (PPAR)gamma have been described in subjects with dominantly inherited severe insulin resistance associated with partial lipodystrophy, hypertension, and dyslipidemia. These mutant receptors behave as dominant-negative inhibitors of PPARgamma signaling when studied in transfected cells. The extent to which such dominant-negative effects extend to signaling through other coexpressed PPAR isoforms has not been evaluated. To examine these issues further, we have created a PPARalpha mutant harboring twin substitutions, Leu459Ala and Glu462Ala, within the ligand binding domain (PPARalpha(mut)), examined its signaling properties, and compared the effects of dominant-negative PPARalpha and PPARgamma mutants on basal and ligand-induced gene transcription in adipocytes and hepatocytes. PPARalpha(mut) was transcriptionally inactive, repressed basal activity from a PPAR response element-containing promoter, inhibited the coactivator function of cotransfected PPAR-gamma coactivator 1alpha, and strongly inhibited the transcriptional response to cotransfected wild-type receptor. In contrast to PPARgamma, wild-type PPARalpha failed to recruit the transcriptional corepressors NCoR and SMRT. However, PPARalpha(mut) avidly recruited these corepressors in a ligand-dissociable manner. In hepatocytes and adipocytes, both PPARalpha(mut) and the corresponding PPARgamma mutant were capable of inhibiting the expression of genes primarily regulated by PPARalpha, -gamma, or -delta ligands, albeit with some differences in potency. Thus, dominant-negative forms of PPARalpha and PPARgamma are capable of interfering with PPAR signaling in a manner that is not wholly restricted to their cognate target genes. These findings may have implications for the pathogenesis of human syndromes resulting from mutations in this family of transcription factors.

Amino Acid Sequence↗
PubMed2006

Phytocomponents of triterpenoids, oleanolic acid and ursolic acid, regulated differently the processing of epidermal keratinocytes via PPAR-alpha pathway.

Naturally occurring triterpenoids such as oleanolic acid (OA) and ursolic acid (UA) are known to have anti-inflammatory and anticarcinogenic activities in some types of cells. Although it has been reported that UA increases the amount of ceramide in keratinocytes, there is little study on the mechanism of triterpenoids involved in the differentiation of keratinocytes as well as their effects on epidermal permeability barrier. A study was therefore conducted to determine whether OA and UA could stimulate the differentiation of epidermal keratinocytes through peroxisome proliferator-activated receptor (PPAR)-alpha activation. This work was then extended to investigate the rate of formation of cornified envelope as a marker in the terminal differentiation of keratinocytes and the amount of transglutaminase in human keratinocytes treated with OA and UA. It was shown that OA induced the differentiation of keratinocytes, whereas UA had little effect. In addition, reporter gene assay using PPAR response element activity demonstrated that OA might be related to the increase of PPAR-alpha activity in CV-1 cells. Moreover, it enhanced the recovery of epidermal permeability barrier function as well as increased ceramides in epidermis after topical application. We therefore propose that the effect of OA on the stimulation of differentiation in epidermal keratinocytes seems to be highly related to activation of PPAR-alpha.

Animals↗
PubMed2002

HMG-CoA reductase inhibition and PPAR- alpha activation both inhibit cyclosporin A induced endothelin-1 secretion in cultured endothelial cells.

The use of cyclosporin A (CsA) in solid organ transplantation has been shown to be associated with the development of hypertension and nephrotoxicity. Several mechanisms, including endothelin (ET)-1-mediated systemic vasoconstriction, are considered to be responsible for CsA-induced hypertension. This study shows that: (i) incubation of CsA (1 microg) with bovine aortic endothelial cells leads to increased ET secretion by+40%; (ii) the use of compactin, the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor and fibric acid, the peroxisome-proliferator-activated receptor (PPAR)-alpha activator, inhibit the CsA-induced ET secretion to the level below the basal ET secretion, by -32% and -26% respectively; (iii) both inhibitions were reversed by the addition of mevalonate, suggesting communication between the HMG-CoA reductase product and PPAR-alpha pathway. The present findings may be of significant clinical relevance, since statins and fibrates beyond their hypolipidaemic action may represent a potential therapeutic tool in the treatment or prophylaxis of CsA-associated side effects. Furthermore, we suggest that the mevalonate metabolism would interfere with PPAR-alpha activity.

Animals↗
PubMed2005

Dual PPAR-alpha and -gamma activators derived from novel benzoxazinone containing thiazolidinediones having antidiabetic and hypolipidemic potential.

2,4-Thiazolidinedione derivatives of 1,3-benzoxazinone were synthesized and evaluated for their PPAR-alpha and -gamma dual activation. DRF-2519, a compound obtained through SAR of TZD derivatives of benzoxazinone, has shown potent dual PPAR activation. In ob/ob mice, it showed better efficacy than the comparator molecules. In fat fed rat model, it showed significant improvement in lipid parameters, which was better than fibrates.

Animals↗
PubMed2006

PPAR-alpha activator fenofibrate increases renal CYP-derived eicosanoid synthesis and improves endothelial dilator function in obese Zucker rats.

Previous studies have shown that the synthesis of renal cytochrome P-450 (CYP)-derived eicosanoids is downregulated in genetic or high-fat diet-induced obese rats. Experiments were designed to determine whether fenofibrate, a peroxisome proliferator-activated receptor (PPAR)-alpha agonist, would induce renal eicosanoid synthesis and improve endothelial function in obese Zucker rats. Administration of fenofibrate (150 mg.kg(-1).day(-1) for 4 wk) significantly reduced plasma insulin, triglyceride, and total cholesterol levels in obese Zucker rats. CYP2C11 and CYP2C23 proteins were downregulated in renal vessels of obese Zucker rats. Consequently, renal vascular epoxygenase activity decreased by 15% in obese Zucker rats compared with lean controls. Chronic fenofibrate treatment significantly increased renal cortical and vascular CYP2C11 and CYP2C23 protein levels in obese Zucker rats, whereas it had no effect on epoxygenase protein and activity in lean Zucker rats. Renal cortical and vascular epoxygenase activities were consequently increased by 54% and 18%, respectively, in fenofibrate-treated obese rats. In addition, acetylcholine (1 microM)-induced vasodilation was significantly reduced in obese Zucker kidneys (37% +/- 11%) compared with lean controls (67% +/- 9%). Chronic fenofibrate administration increased afferent arteriolar responses to 1 microM of acetylcholine in obese Zucker rats (69% +/- 4%). Inhibition of the epoxygenase pathway with 6-(2-propargyloxyphenyl)hexanoic acid attenuated afferent arteriolar diameter responses to acetylcholine to a greater extent in lean compared with obese Zucker rats. These results demonstrate that the PPAR-alpha agonist fenofibrate increased renal CYP-derived eicosanoids and restored endothelial dilator function in obese Zucker rats.

Animals↗
PubMed2005

Efficacy of peroxisome proliferative activated receptor (PPAR)-alpha ligands, fenofibrate, on intimal hyperplasia and constrictive remodeling after coronary angioplasty in porcine models.

Constrictive remodeling and intimal hyperplasia play a prominent role in restenosis after angioplasty. It has been reported that the severity of constrictive remodeling and intimal hyperplasia correlate with adventitial angiogenesis and inflammation. Experimental evidence indicates that inflammation participates in angiogenesis, and therefore inhibition of inflammation may impair neovascularization. We tested whether fenofibrate, peroxisome proliferative activated receptors (PPAR)-alpha specific ligand, inhibits the early inflammation, adventitial angiogenesis, constrictive remodeling and intimal hyperplasia after angioplasty using porcine coronary arteries. Fenofibrate was tested in vivo, in 30 coronary arteries of 10 pigs (1g/day, orally) and was compared to placebo. Quantitative intravascular ultrasound and histopathologic assessment showed that fenofibrate increased lumen (6.28 mm(2) versus 5.15 mm(2)), vessel area (7.34 mm(2) versus 6.69 mm(2)) and inhibited constrictive remodeling. Inflammatory cell infiltration was evaluated with scanning electron microscopy 3 days after angioplasty and was significantly decreased in the treated vessels compared to control. Adventitial angiogenesis 3 days after angioplasty was significantly reduced in the injured vessels derived from the fenofibrate treated group compared to placebo. In conclusion, pharmacological activation of PPAR-alpha inhibited constrictive remodeling and neointimal hyperplasia after angioplasty through inhibition of inflammation and adventitial neovascularization.

Angioplasty, Balloon, Coronary↗
PubMed2006

Pharmacokinetics of muraglitazar (BMS-298585), a dual peroxisome proliferator-activated receptors (PPAR) alpha and gamma activator, in mice, rats, dogs, and monkeys.

The pharmacokinetic parameters of muraglitazar, a novel dual-activator of the peroxisome proliferator-activated receptors (PPAR) alpha and gamma, were determined in mice, rats, dogs, and monkeys after intravenous and oral administration. In the mouse, rat, and monkey the absolute oral bioavailability of muraglitazar ranged from 64 to 88%, and in the dog oral bioavailability was approximately 18%. The systemic clearance values of muraglitazar in the mouse, rat, dog, and cynomolgus monkey were 1.2, 3.0, 12.3 and 1.2 ml min-1 kg-1, respectively. The terminal elimination half-life was 2.4 h in dogs and 7.3 h in rats. The terminal elimination half-life could not be determined in the mouse and monkey because the sampling interval did not adequately cover the terminal elimination phase. Muraglitazar appears to be distributed outside of the vasculature, with the steady-state volume of distribution being approximately twofold that of the vascular volume in rats and dogs, and approximately twofold that of the total body water in mice. The systemic plasma clearance of muraglitazar in humans was predicted to be approximately 12-14 ml min-1 kg-1 based on allometry or by scaling of in vitro clearance parameters. Overall, the pharmacokinetic parameters of muraglitazar in preclinical species were acceptable for the advancement of the compound as a clinical candidate.

Administration, Oral↗