The Experts below are selected from a list of 162 Experts worldwide ranked by ideXlab platform
Mark A Dominick - One of the best experts on this subject based on the ideXlab platform.
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nonclinical safety evaluation of Muraglitazar a novel pparα γ agonist
Toxicological Sciences, 2007Co-Authors: Crystal R Waites, Mark A Dominick, Thomas P Sanderson, Beth E SchillingAbstract:The toxicity of Muraglitazar, an oxybenzylglycine, nonthiazolidinedione peroxisome proliferator-activated receptor (PPAR) α/γ agonist, was evaluated in a comprehensive nonclinical toxicology program that included single-dose oral toxicity studies in mice, rats, and monkeys; repeat-dose toxicity studies in rats, dogs, and monkeys; a battery of in vitro and in vivo genetic toxicity studies; carcinogenicity studies in mice and rats; reproductive and developmental toxicity studies in rats and rabbits; and studies to investigate species-specific findings. Pharmacologically mediated changes, similar to those observed with other PPARγ agonists, were observed following chronic administration and included subcutaneous edema, hematologic/hematopoietic and serum chemistry alterations, and morphologic findings in the heart and adipose tissue in rats and monkeys. In dogs, a species highly sensitive to PPARγ agonists, Muraglitazar caused pronounced species-specific clinical toxicity and degenerative changes in the brain, spinal cord, and testes at high doses and exposures. Muraglitazar was nongenotoxic in the standard battery of genotoxicity studies. Gallbladder adenomas in male mice and adipocyte neoplasms in male and female rats were seen at suprapharmacologic exposures, whereas urinary bladder tumors occurred in male rats at lower exposures. Subsequent investigative studies established that the urinary bladder carcinogenic effect was mediated by urolithiasis rather than a direct pharmacologic effect on urothelium. Muraglitazar had no effects on reproductive function in male and female rats at high systemic exposures, was not teratogenic in rats or rabbits, and demonstrated no selective developmental toxicity. Overall, there were no nonclinical findings that precluded the safe administration of Muraglitazar to humans.
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rodent carcinogenicity profile of the antidiabetic dual ppar α and γ agonist Muraglitazar
Toxicological Sciences, 2007Co-Authors: Sarah H Tannehillgregg, Thomas P Sanderson, Beth E Schilling, Lora L Arnold, Robbie C Waites, Daniel Minnema, Richard W Voelker, Borge M Ulland, Samuel M Cohen, Mark A DominickAbstract:The carcinogenic potential of Muraglitazar, a dual human peroxisome proliferator-activated receptor alpha/gamma agonist, was evaluated in 2-year studies in mice (1, 5, 20, and 40 mg/kg) and rats (1, 5, 30, and 50 mg/kg). Benign gallbladder adenomas occurred at low incidences in male mice at 20 and 40 mg/kg (area under the curve [AUC] exposures > or = 62 times human exposure at 5 mg/day) and were considered drug related due to an increased incidence of gallbladder mucosal hyperplasia at these doses. There was a dose-related increased incidence of transitional cell papilloma and carcinoma of the urinary bladder in male rats at 5, 30, and 50 mg/kg (AUC exposures > or = 8 times human exposure at 5 mg/day). At 30 and 50 mg/kg, the urinary bladder tumors were accompanied by evidence of increased urine solids. Subsequent investigative studies established that the urinary bladder carcinogenic effect was mediated by urolithiasis rather than a direct pharmacologic effect on urothelium. Incidences of subcutaneous liposarcoma in male rats and subcutaneous lipoma in female rats were increased at 50 mg/kg (AUC exposures > or = 48 times human exposure at 5 mg/day) and attributed, in part, to persistent pharmacologic stimulation of preadipocytes. Toxicologically relevant nonneoplastic changes in target tissues included thinning of cortical bone in mice and hyperplastic and metaplastic adipocyte changes in mice and rats. Considering that Muraglitazar is nongenotoxic, the observed tumorigenic effects in mice and rats have no established clinical relevance since they occurred at either clinically nonrelevant exposures (gallbladder and adipose tumors) or by a species-specific mechanism (urinary bladder tumors).
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subchronic urinary bladder effects of Muraglitazar in male rats
Toxicological Sciences, 2007Co-Authors: Terry Van Vleet, Thomas P Sanderson, Beth E Schilling, Samuel M Cohen, Lora L Arnold, M Cano, Randy M White, Robbie C Waites, James Mitroka, Mark A DominickAbstract:Muraglitazar, a PPARa/g dual agonist, was dosed orally to rats once daily for 13 weeks to evaluate urinary and urothelial changes of potential relevance to urinary bladder tumorigenesis. Groups of 17 young or aged rats per sex were fed a normal or 1% NH4Clsupplemented diet and were dosed with 0, 1, or 50 mg/kg Muraglitazar. Lithogenic ions and sediment were profiled from freshly voided urine samples collected 24 h after dosing, and drug exposures were measured. Urinary citrate, oxalate, and epidermal growth factor (EGF) were assayed from 18-h urine collections. Urothelium was assessed by light microscopy, scanning electron microscopy, and BrdU and TUNEL immunohistochemistry. When fed a normal diet, urine pH was higher in males (above 6.5). Urine volume/body weight was greater in females. Urine soluble/total calcium and magnesium and phosphorus/creatinine ratios were lower in male rats fed a normal diet. Urine citrate levels were decreased and oxalate was increased in young male rats treated with 50 mg/kg Muraglitazar compared to age/sex/diet-matched controls. No changes in urine sediment were detected 24 h after dosing. In young male rats treated with 50 mg/kg on normal diet, multifocal urothelial necrosis and proliferation were observed, whereas urothelial apoptosis and urine EGF levels were unchanged compared to age/sex/diet-matched controls. Urothelial necrosis and proliferation were not correlated to systemic or urinary drug exposures and were prevented by dietary acidification. These data suggest that Muraglitazar-associated changes in urine composition predispose to urothelial cytotoxicity and proliferation in the urinary bladder of young male rats and that urine sediment must be profiled at multiple daily timepoints to fully
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urothelial carcinogenesis in the urinary bladder of male rats treated with Muraglitazar a ppar alpha gamma agonist evidence for urolithiasis as the inciting event in the mode of action
Toxicologic Pathology, 2006Co-Authors: Mark A Dominick, Thomas P Sanderson, Melvin R White, Terry Van Vleet, Samuel M Cohen, Lora L Arnold, M Cano, Sarah H Tannehillgregg, Jeffrey D Moehlenkamp, Crystal R WaitesAbstract:Muraglitazar, a PPARalpha/gamma agonist, dose-dependently increased urinary bladder tumors in male Harlan Sprague-Dawley (HSD) rats administered 5, 30, or 50 mg/kg/day for up to 2 years. To determine the mode of tumor development, male HSD rats were treated daily for up to 21 months at doses of 0, 1, or 50 mg/kg while being fed either a normal or 1% NH4Cl-acidified diet. Muraglitazar-associated, time-dependent changes in urine composition, urothelial mitogenesis and apoptosis, and urothelial morphology were assessed. In control and treated rats fed a normal diet, urine pH was generally > or = 6.5, which facilitates formation of calcium-and magnesium-containing solids, particularly in the presence of other prolithogenic changes in rat urine. Urinary citrate, an inhibitor of lithogenesis, and soluble calcium concentrations were dose dependently decreased in association with increased calcium phosphate precipitate, crystals and/or microcalculi; magnesium ammonium phosphate crystals and aggregates; and calcium oxalate-containing thin, rod-like crystals. Morphologically, sustained urothelial cytotoxicity and proliferation with a ventral bladder predilection were noted in treated rats by month 1 and urinary carcinomas with a similar distribution occurred by month 9. Urothelial apoptotic rates were unaffected by Muraglitazar treatment or diet. In Muraglitazar-treated rats fed an acidified diet, urine pH was invariably < 6.5, which inhibited formation of calcium-and magnesium-containing solids. Moreover, dietary acidification prevented the urothelial cytotoxic, proliferative, and tumorigenic responses. Collectively, these data support an indirect pharmacologic mode of urinary bladder tumor development involving alterations in urine composition that predispose to urolithiasis and associated decreases in urine-soluble calcium concentrations.
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urothelial carcinogenesis in the urinary bladder of male rats treated with Muraglitazar a pparα γ agonist evidence for urolithiasis as the inciting event in the mode of action
Toxicologic Pathology, 2006Co-Authors: Mark A Dominick, Thomas P Sanderson, Melvin R White, Terry Van Vleet, Samuel M Cohen, Lora L Arnold, M Cano, Sarah H Tannehillgregg, Jeffrey D Moehlenkamp, Crystal R WaitesAbstract:Muraglitazar, a PPARα/γ agonist, dose-dependently increased urinary bladder tumors in male Harlan Sprague–Dawley (HSD) rats administered 5, 30, or 50 mg/kg/day for up to 2 years. To determine the mode of tumor development, male HSD rats were treated daily for up to 21 months at doses of 0, 1, or 50 mg/kg while being fed either a normal or 1% NH4Cl-acidified diet. Muraglitazar-associated, time-dependent changes in urine composition, urothelial mitogenesis and apoptosis, and urothelial morphology were assessed. In control and treated rats fed a normal diet, urine pH was generally ≥6.5, which facilitates formation of calcium- and magnesium-containing solids, particularly in the presence of other prolithogenic changes in rat urine. Urinary citrate, an inhibitor of lithogenesis, and soluble calcium concentrations were dose dependently decreased in association with increased calcium phosphate precipitate, crystals and/or microcalculi; magnesium ammonium phosphate crystals and aggregates; and calcium oxalate-con...
Griffith W Humphreys - One of the best experts on this subject based on the ideXlab platform.
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involvement of multiple cytochrome p450 and udp glucuronosyltransferase enzymes in the in vitro metabolism of Muraglitazar
Drug Metabolism and Disposition, 2007Co-Authors: Donglu Zhang, Lifei Wang, Gamini Chandrasena, Mingshe Zhu, Hongjian Zhang, Carl D Davis, Griffith W HumphreysAbstract:Muraglitazar (Pargluva), a dual α/γ peroxisome proliferator-activated receptor activator, has both glucose- and lipid-lowering effects in animal models and in patients with diabetes. The human major primary metabolic pathways of Muraglitazar include acylglucuronidation, aliphatic/aryl hydroxylation, and O-demethylation. This study describes the identification of human cytochrome P450 (P450) and UDP-glucuronosyltransferase (UGT) enzymes involved in the in vitro metabolism of Muraglitazar. [14C]Muraglitazar was metabolized by cDNA-expressed CYP2C8, 2C9, 2C19, 2D6, and 3A4, but to a very minimal extent by CYP1A2, 2A6, 2B6, 2C18, 2E1, and 3A5. Inhibition of the in vitro metabolism of Muraglitazar in human liver microsomes, at a clinically efficacious concentration, by chemical inhibitors and monoclonal antibodies further supported involvement of CYP2C8, 2C9, 2C19, 2D6, and 3A4 in its oxidation. A combination of intrinsic clearance (Vmax/Km) and relative concentrations of each P450 enzyme in the human liver was used to predict the contribution of CYP2C8, 2C9, 2C19, 2D6, and 3A4 to the formation of each primary oxidative metabolite and to the overall oxidative metabolism of Muraglitazar. Glucuronidation of [14C]Muraglitazar was catalyzed by cDNA-expressed UGT1A1, 1A3, and 1A9, but not by UGT1A6, 1A8, 1A10, 2B4, 2B7, and 2B15. The Km values for Muraglitazar glucuronidation by the three active UGT enzymes were similar (2–4 μM). In summary, Muraglitazar was metabolized by multiple P450 and UGT enzymes to form multiple metabolites. This characteristic predicts a low potential for the alteration of the pharmacokinetic parameters of Muraglitazar via polymorphic drug metabolism enzymes responsible for clearance of the compound or by coadministration of drugs that inhibit or induce relevant metabolic enzymes.
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pharmacokinetics of Muraglitazar bms 298585 a dual peroxisome proliferator activated receptors ppar alpha and gamma activator in mice rats dogs and monkeys
Xenobiotica, 2006Co-Authors: V P Hosagrahara, Gamini Chandrasena, Peter T W Cheng, Shuying Chang, Barry Koplowitz, Narayanan Hariharan, Griffith W HumphreysAbstract:The pharmacokinetic parameters of Muraglitazar, a novel dual-activator of the peroxisome proliferator-activated receptors (PPAR) α and γ, 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 wa...
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biotransformation of carbon 14 labeled Muraglitazar in male mice interspecies difference in metabolic pathways leading to unique metabolites
Drug Metabolism and Disposition, 2006Co-Authors: Donglu Zhang, Lifei Wang, Hao Zhang, Peter T W Cheng, Duxi Zhang, Donald W Everett, Griffith W HumphreysAbstract:Muraglitazar (Pargluva; Bristol-Myers Squibb), a dual α/γ peroxisome proliferator-activated receptor activator, is under development for treatment of type 2 diabetes. This study describes the biotransformation profile of carbon-14-labeled Muraglitazar in plasma, urine, feces, and bile samples from male CD-1 mice [intact and bile duct cannulation (BDC)] after single oral doses of 1 and 40 mg/kg. The major drug-related component circulating in mouse plasma was the parent compound for up to 4 h postdose. Similar to excretion profiles of Muraglitazar in humans, monkeys, and rats, urinary excretion was the minor and fecal excretion via the biliary route was the major elimination pathway for Muraglitazar in mice. The parent compound was a minor component in urine, bile, and feces, indicating that Muraglitazar was extensively metabolized in mice. Major biotransformation pathways of Muraglitazar in mice included taurine conjugate formation, acyl glucuronidation, hydroxylation, and O -dealkylation. In addition to those metabolites previously identified in humans, monkeys, and rats (M1–M21), several unique metabolites identified in mice included taurine conjugates (M24, M25, M26a,b,c, and M31), oxazole-ring-opened metabolites (M27 and M28), glutathione conjugates (M29a,b and M30), a dihydroxylated metabolite (M32), hydroxylated metabolites (M33 and M35), and a dehydrogenated metabolite (M34). The taurine conjugate of Muraglitazar, M24, was a major metabolite in mice, accounting for 12 to 15% of the total dose in BDC mice or 7 to 12% of the total dose in intact mice. None of these taurine and glutathione conjugates were found in the bile samples of humans, monkeys, or rats.
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glucuronidation as a major metabolic clearance pathway of 14c labeled Muraglitazar in humans metabolic profiles in subjects with or without bile collection
Drug Metabolism and Disposition, 2006Co-Authors: Lifei Wang, Donglu Zhang, Arun Swaminathan, Peter T W Cheng, Donald W Everett, Yongjun Xue, Rogelio Mosquedagarcia, Catherine Aurang, Griffith W HumphreysAbstract:The metabolism and disposition of 14C-labeled Muraglitazar (Pargluva), a novel dual α/γ peroxisome proliferator-activated receptor activator, was investigated in eight healthy male subjects with and without bile collection (groups 1 and 2) after a single 20-mg oral dose. Bile samples were collected for 3 to 8 h after dosing from group 2 subjects in addition to the urine and feces collection. In plasma, the parent compound was the major component, and circulating metabolites, including several glucuronide conjugates, were minor components at all time points. The exposure to parent drug ( C max and area under the plasma concentration versus time curve) in subjects with bile collection was generally lower than that in subjects without bile collection. The major portion of the radioactive dose was recovered in feces (91% for group 1 and 51% for group 2). In addition, 40% of the dose was recovered in the bile from group 2 subjects. In this 3- to 8-h bile, the glucuronide of Muraglitazar (M13, 15% of dose) and the glucuronides of its oxidative metabolites (M17a,b,c, M18a,b,c, and M20, together, 16% of dose) accounted for approximately 80% of the biliary radioactivity; Muraglitazar and its O -demethylated metabolite (M15) each accounted for approximately 4% of the dose. In contrast, fecal samples only contained Muraglitazar and its oxidative metabolites, suggesting hydrolysis of biliary glucuronides in the intestine before fecal excretion. Thus, the subjects with and without bile collection showed different metabolic profiles of Muraglitazar after oral administration, and glucuronidation was not observed as a major pathway of metabolic clearance from subjects with the conventional urine and fecal collection, but was found as a major elimination pathway from subjects with bile collection.
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structural elucidation of human oxidative metabolites of Muraglitazar use of microbial bioreactors in the biosynthesis of metabolite standards
Drug Metabolism and Disposition, 2006Co-Authors: Donglu Zhang, Haiying Zhang, Mingshe Zhu, Arun Swaminathan, Peter T W Cheng, Samuel J Bonacorsi, Nelly Aranibar, Ronald L Hanson, Yande Huang, Griffith W HumphreysAbstract:Muraglitazar (Pargluva), a dual α/γ peroxisome proliferator-activated receptor activator, is currently in clinical development for treatment of type 2 diabetes. This study describes the structural elucidation of the human oxidative metabolites of Muraglitazar through the use of a combination of microbial bioreactors, NMR and accurate mass analyses, and organic synthesis. Plasma, urine, and feces were collected from six healthy subjects following oral administration of 14C-labeled Muraglitazar (10 mg, 100 μCi) and pooled samples were analyzed. Approximately 96% of the recovered radioactive dose was found in the feces and 3.5% in the urine. The parent compound represented >85% of the radioactivity in plasma. The fecal radioactivity was distributed among 16 metabolites (M1–M12, M14–M16, and M8a) and the parent drug, of which hydroxylation and O-demethylation metabolites (M5, M10, M11, M14, and M15) represented the prominent human metabolites. The urinary radioactivity was distributed into several peaks including Muraglitazar glucuronide (M13) and the parent drug. Low concentrations of metabolites in human samples prevented direct identification of metabolites beyond liquid chromatographic (LC)-mass spectrometric analysis. Microbial strains Cunninghamella elegans and Saccharopolyspora hirsuta produced Muraglitazar metabolites that had the same high performance liquid chromatography retention times and the same tandem mass spectrometric (MS/MS) properties as the corresponding human metabolites. The microbial metabolites M9, M10, M11, M14, M15, and M16 were isolated and analyzed by NMR. Based on these LC-MS/MS and NMR analyses, and organic synthesis, the structures of 16 human oxidative metabolites were identified. The oxidative metabolism of Muraglitazar was characterized by hydroxylation, O-demethylation, oxazolering opening, and O-demethylation/hydroxylation, as well as O-dealkylation and carboxylic acid formation. This study demonstrated the utility of microbial bioreactors for the identification of metabolites.
Crystal R Waites - One of the best experts on this subject based on the ideXlab platform.
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nonclinical safety evaluation of Muraglitazar a novel pparα γ agonist
Toxicological Sciences, 2007Co-Authors: Crystal R Waites, Mark A Dominick, Thomas P Sanderson, Beth E SchillingAbstract:The toxicity of Muraglitazar, an oxybenzylglycine, nonthiazolidinedione peroxisome proliferator-activated receptor (PPAR) α/γ agonist, was evaluated in a comprehensive nonclinical toxicology program that included single-dose oral toxicity studies in mice, rats, and monkeys; repeat-dose toxicity studies in rats, dogs, and monkeys; a battery of in vitro and in vivo genetic toxicity studies; carcinogenicity studies in mice and rats; reproductive and developmental toxicity studies in rats and rabbits; and studies to investigate species-specific findings. Pharmacologically mediated changes, similar to those observed with other PPARγ agonists, were observed following chronic administration and included subcutaneous edema, hematologic/hematopoietic and serum chemistry alterations, and morphologic findings in the heart and adipose tissue in rats and monkeys. In dogs, a species highly sensitive to PPARγ agonists, Muraglitazar caused pronounced species-specific clinical toxicity and degenerative changes in the brain, spinal cord, and testes at high doses and exposures. Muraglitazar was nongenotoxic in the standard battery of genotoxicity studies. Gallbladder adenomas in male mice and adipocyte neoplasms in male and female rats were seen at suprapharmacologic exposures, whereas urinary bladder tumors occurred in male rats at lower exposures. Subsequent investigative studies established that the urinary bladder carcinogenic effect was mediated by urolithiasis rather than a direct pharmacologic effect on urothelium. Muraglitazar had no effects on reproductive function in male and female rats at high systemic exposures, was not teratogenic in rats or rabbits, and demonstrated no selective developmental toxicity. Overall, there were no nonclinical findings that precluded the safe administration of Muraglitazar to humans.
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urothelial carcinogenesis in the urinary bladder of male rats treated with Muraglitazar a ppar alpha gamma agonist evidence for urolithiasis as the inciting event in the mode of action
Toxicologic Pathology, 2006Co-Authors: Mark A Dominick, Thomas P Sanderson, Melvin R White, Terry Van Vleet, Samuel M Cohen, Lora L Arnold, M Cano, Sarah H Tannehillgregg, Jeffrey D Moehlenkamp, Crystal R WaitesAbstract:Muraglitazar, a PPARalpha/gamma agonist, dose-dependently increased urinary bladder tumors in male Harlan Sprague-Dawley (HSD) rats administered 5, 30, or 50 mg/kg/day for up to 2 years. To determine the mode of tumor development, male HSD rats were treated daily for up to 21 months at doses of 0, 1, or 50 mg/kg while being fed either a normal or 1% NH4Cl-acidified diet. Muraglitazar-associated, time-dependent changes in urine composition, urothelial mitogenesis and apoptosis, and urothelial morphology were assessed. In control and treated rats fed a normal diet, urine pH was generally > or = 6.5, which facilitates formation of calcium-and magnesium-containing solids, particularly in the presence of other prolithogenic changes in rat urine. Urinary citrate, an inhibitor of lithogenesis, and soluble calcium concentrations were dose dependently decreased in association with increased calcium phosphate precipitate, crystals and/or microcalculi; magnesium ammonium phosphate crystals and aggregates; and calcium oxalate-containing thin, rod-like crystals. Morphologically, sustained urothelial cytotoxicity and proliferation with a ventral bladder predilection were noted in treated rats by month 1 and urinary carcinomas with a similar distribution occurred by month 9. Urothelial apoptotic rates were unaffected by Muraglitazar treatment or diet. In Muraglitazar-treated rats fed an acidified diet, urine pH was invariably < 6.5, which inhibited formation of calcium-and magnesium-containing solids. Moreover, dietary acidification prevented the urothelial cytotoxic, proliferative, and tumorigenic responses. Collectively, these data support an indirect pharmacologic mode of urinary bladder tumor development involving alterations in urine composition that predispose to urolithiasis and associated decreases in urine-soluble calcium concentrations.
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urothelial carcinogenesis in the urinary bladder of male rats treated with Muraglitazar a pparα γ agonist evidence for urolithiasis as the inciting event in the mode of action
Toxicologic Pathology, 2006Co-Authors: Mark A Dominick, Thomas P Sanderson, Melvin R White, Terry Van Vleet, Samuel M Cohen, Lora L Arnold, M Cano, Sarah H Tannehillgregg, Jeffrey D Moehlenkamp, Crystal R WaitesAbstract:Muraglitazar, a PPARα/γ agonist, dose-dependently increased urinary bladder tumors in male Harlan Sprague–Dawley (HSD) rats administered 5, 30, or 50 mg/kg/day for up to 2 years. To determine the mode of tumor development, male HSD rats were treated daily for up to 21 months at doses of 0, 1, or 50 mg/kg while being fed either a normal or 1% NH4Cl-acidified diet. Muraglitazar-associated, time-dependent changes in urine composition, urothelial mitogenesis and apoptosis, and urothelial morphology were assessed. In control and treated rats fed a normal diet, urine pH was generally ≥6.5, which facilitates formation of calcium- and magnesium-containing solids, particularly in the presence of other prolithogenic changes in rat urine. Urinary citrate, an inhibitor of lithogenesis, and soluble calcium concentrations were dose dependently decreased in association with increased calcium phosphate precipitate, crystals and/or microcalculi; magnesium ammonium phosphate crystals and aggregates; and calcium oxalate-con...
Lora L Arnold - One of the best experts on this subject based on the ideXlab platform.
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effects of pioglitazone a peroxisome proliferator activated receptor gamma agonist on the urine and urothelium of the rat
Toxicological Sciences, 2010Co-Authors: Shugo Suzuki, Lora L Arnold, Karen L Pennington, Satoko Kakiuchikiyota, Min Wei, Hideki Wanibuchi, Samuel M CohenAbstract:Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors, which belong to the nuclear receptor superfamily. Some PPARgamma agonists, such as pioglitazone, and dual PPARgamma/PPARalpha agonists, such as Muraglitazar, induced urothelial bladder tumors in rats but not in mice. In this study, we investigated the early effects in the urine and bladder of rats treated with pioglitazone to evaluate the possible relation between urinary solids formation and urothelial cytotoxicity and regenerative proliferation. In a 4-week experiment, treatment of rats with 16 mg/kg pioglitazone induced cytotoxicity and necrosis of the urothelial superficial layer, with increased cell proliferation measured by bromodeoxyuridine labeling index and hyperplasia by histology. It also produced alterations in urinary solid formation, especially calcium-containing crystals and calculi. PPARgamma agonists (pioglitazone and troglitazone) in vitro reduced rat urothelial cell proliferation and induced uroplakin synthesis, a specific differentiation marker in urothelial cells. Our data support the hypothesis that the bladder tumors produced in rats by pioglitazone are related to the formation of urinary solids. This strongly supports the previous conclusion in studies with Muraglitazar that this is a rat-specific phenomenon and does not pose a urinary bladder cancer risk to humans treated with these agents.
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rodent carcinogenicity profile of the antidiabetic dual ppar α and γ agonist Muraglitazar
Toxicological Sciences, 2007Co-Authors: Sarah H Tannehillgregg, Thomas P Sanderson, Beth E Schilling, Lora L Arnold, Robbie C Waites, Daniel Minnema, Richard W Voelker, Borge M Ulland, Samuel M Cohen, Mark A DominickAbstract:The carcinogenic potential of Muraglitazar, a dual human peroxisome proliferator-activated receptor alpha/gamma agonist, was evaluated in 2-year studies in mice (1, 5, 20, and 40 mg/kg) and rats (1, 5, 30, and 50 mg/kg). Benign gallbladder adenomas occurred at low incidences in male mice at 20 and 40 mg/kg (area under the curve [AUC] exposures > or = 62 times human exposure at 5 mg/day) and were considered drug related due to an increased incidence of gallbladder mucosal hyperplasia at these doses. There was a dose-related increased incidence of transitional cell papilloma and carcinoma of the urinary bladder in male rats at 5, 30, and 50 mg/kg (AUC exposures > or = 8 times human exposure at 5 mg/day). At 30 and 50 mg/kg, the urinary bladder tumors were accompanied by evidence of increased urine solids. Subsequent investigative studies established that the urinary bladder carcinogenic effect was mediated by urolithiasis rather than a direct pharmacologic effect on urothelium. Incidences of subcutaneous liposarcoma in male rats and subcutaneous lipoma in female rats were increased at 50 mg/kg (AUC exposures > or = 48 times human exposure at 5 mg/day) and attributed, in part, to persistent pharmacologic stimulation of preadipocytes. Toxicologically relevant nonneoplastic changes in target tissues included thinning of cortical bone in mice and hyperplastic and metaplastic adipocyte changes in mice and rats. Considering that Muraglitazar is nongenotoxic, the observed tumorigenic effects in mice and rats have no established clinical relevance since they occurred at either clinically nonrelevant exposures (gallbladder and adipose tumors) or by a species-specific mechanism (urinary bladder tumors).
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subchronic urinary bladder effects of Muraglitazar in male rats
Toxicological Sciences, 2007Co-Authors: Terry Van Vleet, Thomas P Sanderson, Beth E Schilling, Samuel M Cohen, Lora L Arnold, M Cano, Randy M White, Robbie C Waites, James Mitroka, Mark A DominickAbstract:Muraglitazar, a PPARa/g dual agonist, was dosed orally to rats once daily for 13 weeks to evaluate urinary and urothelial changes of potential relevance to urinary bladder tumorigenesis. Groups of 17 young or aged rats per sex were fed a normal or 1% NH4Clsupplemented diet and were dosed with 0, 1, or 50 mg/kg Muraglitazar. Lithogenic ions and sediment were profiled from freshly voided urine samples collected 24 h after dosing, and drug exposures were measured. Urinary citrate, oxalate, and epidermal growth factor (EGF) were assayed from 18-h urine collections. Urothelium was assessed by light microscopy, scanning electron microscopy, and BrdU and TUNEL immunohistochemistry. When fed a normal diet, urine pH was higher in males (above 6.5). Urine volume/body weight was greater in females. Urine soluble/total calcium and magnesium and phosphorus/creatinine ratios were lower in male rats fed a normal diet. Urine citrate levels were decreased and oxalate was increased in young male rats treated with 50 mg/kg Muraglitazar compared to age/sex/diet-matched controls. No changes in urine sediment were detected 24 h after dosing. In young male rats treated with 50 mg/kg on normal diet, multifocal urothelial necrosis and proliferation were observed, whereas urothelial apoptosis and urine EGF levels were unchanged compared to age/sex/diet-matched controls. Urothelial necrosis and proliferation were not correlated to systemic or urinary drug exposures and were prevented by dietary acidification. These data suggest that Muraglitazar-associated changes in urine composition predispose to urothelial cytotoxicity and proliferation in the urinary bladder of young male rats and that urine sediment must be profiled at multiple daily timepoints to fully
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urothelial carcinogenesis in the urinary bladder of male rats treated with Muraglitazar a ppar alpha gamma agonist evidence for urolithiasis as the inciting event in the mode of action
Toxicologic Pathology, 2006Co-Authors: Mark A Dominick, Thomas P Sanderson, Melvin R White, Terry Van Vleet, Samuel M Cohen, Lora L Arnold, M Cano, Sarah H Tannehillgregg, Jeffrey D Moehlenkamp, Crystal R WaitesAbstract:Muraglitazar, a PPARalpha/gamma agonist, dose-dependently increased urinary bladder tumors in male Harlan Sprague-Dawley (HSD) rats administered 5, 30, or 50 mg/kg/day for up to 2 years. To determine the mode of tumor development, male HSD rats were treated daily for up to 21 months at doses of 0, 1, or 50 mg/kg while being fed either a normal or 1% NH4Cl-acidified diet. Muraglitazar-associated, time-dependent changes in urine composition, urothelial mitogenesis and apoptosis, and urothelial morphology were assessed. In control and treated rats fed a normal diet, urine pH was generally > or = 6.5, which facilitates formation of calcium-and magnesium-containing solids, particularly in the presence of other prolithogenic changes in rat urine. Urinary citrate, an inhibitor of lithogenesis, and soluble calcium concentrations were dose dependently decreased in association with increased calcium phosphate precipitate, crystals and/or microcalculi; magnesium ammonium phosphate crystals and aggregates; and calcium oxalate-containing thin, rod-like crystals. Morphologically, sustained urothelial cytotoxicity and proliferation with a ventral bladder predilection were noted in treated rats by month 1 and urinary carcinomas with a similar distribution occurred by month 9. Urothelial apoptotic rates were unaffected by Muraglitazar treatment or diet. In Muraglitazar-treated rats fed an acidified diet, urine pH was invariably < 6.5, which inhibited formation of calcium-and magnesium-containing solids. Moreover, dietary acidification prevented the urothelial cytotoxic, proliferative, and tumorigenic responses. Collectively, these data support an indirect pharmacologic mode of urinary bladder tumor development involving alterations in urine composition that predispose to urolithiasis and associated decreases in urine-soluble calcium concentrations.
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urothelial carcinogenesis in the urinary bladder of male rats treated with Muraglitazar a pparα γ agonist evidence for urolithiasis as the inciting event in the mode of action
Toxicologic Pathology, 2006Co-Authors: Mark A Dominick, Thomas P Sanderson, Melvin R White, Terry Van Vleet, Samuel M Cohen, Lora L Arnold, M Cano, Sarah H Tannehillgregg, Jeffrey D Moehlenkamp, Crystal R WaitesAbstract:Muraglitazar, a PPARα/γ agonist, dose-dependently increased urinary bladder tumors in male Harlan Sprague–Dawley (HSD) rats administered 5, 30, or 50 mg/kg/day for up to 2 years. To determine the mode of tumor development, male HSD rats were treated daily for up to 21 months at doses of 0, 1, or 50 mg/kg while being fed either a normal or 1% NH4Cl-acidified diet. Muraglitazar-associated, time-dependent changes in urine composition, urothelial mitogenesis and apoptosis, and urothelial morphology were assessed. In control and treated rats fed a normal diet, urine pH was generally ≥6.5, which facilitates formation of calcium- and magnesium-containing solids, particularly in the presence of other prolithogenic changes in rat urine. Urinary citrate, an inhibitor of lithogenesis, and soluble calcium concentrations were dose dependently decreased in association with increased calcium phosphate precipitate, crystals and/or microcalculi; magnesium ammonium phosphate crystals and aggregates; and calcium oxalate-con...
Thomas P Sanderson - One of the best experts on this subject based on the ideXlab platform.
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nonclinical safety evaluation of Muraglitazar a novel pparα γ agonist
Toxicological Sciences, 2007Co-Authors: Crystal R Waites, Mark A Dominick, Thomas P Sanderson, Beth E SchillingAbstract:The toxicity of Muraglitazar, an oxybenzylglycine, nonthiazolidinedione peroxisome proliferator-activated receptor (PPAR) α/γ agonist, was evaluated in a comprehensive nonclinical toxicology program that included single-dose oral toxicity studies in mice, rats, and monkeys; repeat-dose toxicity studies in rats, dogs, and monkeys; a battery of in vitro and in vivo genetic toxicity studies; carcinogenicity studies in mice and rats; reproductive and developmental toxicity studies in rats and rabbits; and studies to investigate species-specific findings. Pharmacologically mediated changes, similar to those observed with other PPARγ agonists, were observed following chronic administration and included subcutaneous edema, hematologic/hematopoietic and serum chemistry alterations, and morphologic findings in the heart and adipose tissue in rats and monkeys. In dogs, a species highly sensitive to PPARγ agonists, Muraglitazar caused pronounced species-specific clinical toxicity and degenerative changes in the brain, spinal cord, and testes at high doses and exposures. Muraglitazar was nongenotoxic in the standard battery of genotoxicity studies. Gallbladder adenomas in male mice and adipocyte neoplasms in male and female rats were seen at suprapharmacologic exposures, whereas urinary bladder tumors occurred in male rats at lower exposures. Subsequent investigative studies established that the urinary bladder carcinogenic effect was mediated by urolithiasis rather than a direct pharmacologic effect on urothelium. Muraglitazar had no effects on reproductive function in male and female rats at high systemic exposures, was not teratogenic in rats or rabbits, and demonstrated no selective developmental toxicity. Overall, there were no nonclinical findings that precluded the safe administration of Muraglitazar to humans.
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rodent carcinogenicity profile of the antidiabetic dual ppar α and γ agonist Muraglitazar
Toxicological Sciences, 2007Co-Authors: Sarah H Tannehillgregg, Thomas P Sanderson, Beth E Schilling, Lora L Arnold, Robbie C Waites, Daniel Minnema, Richard W Voelker, Borge M Ulland, Samuel M Cohen, Mark A DominickAbstract:The carcinogenic potential of Muraglitazar, a dual human peroxisome proliferator-activated receptor alpha/gamma agonist, was evaluated in 2-year studies in mice (1, 5, 20, and 40 mg/kg) and rats (1, 5, 30, and 50 mg/kg). Benign gallbladder adenomas occurred at low incidences in male mice at 20 and 40 mg/kg (area under the curve [AUC] exposures > or = 62 times human exposure at 5 mg/day) and were considered drug related due to an increased incidence of gallbladder mucosal hyperplasia at these doses. There was a dose-related increased incidence of transitional cell papilloma and carcinoma of the urinary bladder in male rats at 5, 30, and 50 mg/kg (AUC exposures > or = 8 times human exposure at 5 mg/day). At 30 and 50 mg/kg, the urinary bladder tumors were accompanied by evidence of increased urine solids. Subsequent investigative studies established that the urinary bladder carcinogenic effect was mediated by urolithiasis rather than a direct pharmacologic effect on urothelium. Incidences of subcutaneous liposarcoma in male rats and subcutaneous lipoma in female rats were increased at 50 mg/kg (AUC exposures > or = 48 times human exposure at 5 mg/day) and attributed, in part, to persistent pharmacologic stimulation of preadipocytes. Toxicologically relevant nonneoplastic changes in target tissues included thinning of cortical bone in mice and hyperplastic and metaplastic adipocyte changes in mice and rats. Considering that Muraglitazar is nongenotoxic, the observed tumorigenic effects in mice and rats have no established clinical relevance since they occurred at either clinically nonrelevant exposures (gallbladder and adipose tumors) or by a species-specific mechanism (urinary bladder tumors).
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subchronic urinary bladder effects of Muraglitazar in male rats
Toxicological Sciences, 2007Co-Authors: Terry Van Vleet, Thomas P Sanderson, Beth E Schilling, Samuel M Cohen, Lora L Arnold, M Cano, Randy M White, Robbie C Waites, James Mitroka, Mark A DominickAbstract:Muraglitazar, a PPARa/g dual agonist, was dosed orally to rats once daily for 13 weeks to evaluate urinary and urothelial changes of potential relevance to urinary bladder tumorigenesis. Groups of 17 young or aged rats per sex were fed a normal or 1% NH4Clsupplemented diet and were dosed with 0, 1, or 50 mg/kg Muraglitazar. Lithogenic ions and sediment were profiled from freshly voided urine samples collected 24 h after dosing, and drug exposures were measured. Urinary citrate, oxalate, and epidermal growth factor (EGF) were assayed from 18-h urine collections. Urothelium was assessed by light microscopy, scanning electron microscopy, and BrdU and TUNEL immunohistochemistry. When fed a normal diet, urine pH was higher in males (above 6.5). Urine volume/body weight was greater in females. Urine soluble/total calcium and magnesium and phosphorus/creatinine ratios were lower in male rats fed a normal diet. Urine citrate levels were decreased and oxalate was increased in young male rats treated with 50 mg/kg Muraglitazar compared to age/sex/diet-matched controls. No changes in urine sediment were detected 24 h after dosing. In young male rats treated with 50 mg/kg on normal diet, multifocal urothelial necrosis and proliferation were observed, whereas urothelial apoptosis and urine EGF levels were unchanged compared to age/sex/diet-matched controls. Urothelial necrosis and proliferation were not correlated to systemic or urinary drug exposures and were prevented by dietary acidification. These data suggest that Muraglitazar-associated changes in urine composition predispose to urothelial cytotoxicity and proliferation in the urinary bladder of young male rats and that urine sediment must be profiled at multiple daily timepoints to fully
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urothelial carcinogenesis in the urinary bladder of male rats treated with Muraglitazar a ppar alpha gamma agonist evidence for urolithiasis as the inciting event in the mode of action
Toxicologic Pathology, 2006Co-Authors: Mark A Dominick, Thomas P Sanderson, Melvin R White, Terry Van Vleet, Samuel M Cohen, Lora L Arnold, M Cano, Sarah H Tannehillgregg, Jeffrey D Moehlenkamp, Crystal R WaitesAbstract:Muraglitazar, a PPARalpha/gamma agonist, dose-dependently increased urinary bladder tumors in male Harlan Sprague-Dawley (HSD) rats administered 5, 30, or 50 mg/kg/day for up to 2 years. To determine the mode of tumor development, male HSD rats were treated daily for up to 21 months at doses of 0, 1, or 50 mg/kg while being fed either a normal or 1% NH4Cl-acidified diet. Muraglitazar-associated, time-dependent changes in urine composition, urothelial mitogenesis and apoptosis, and urothelial morphology were assessed. In control and treated rats fed a normal diet, urine pH was generally > or = 6.5, which facilitates formation of calcium-and magnesium-containing solids, particularly in the presence of other prolithogenic changes in rat urine. Urinary citrate, an inhibitor of lithogenesis, and soluble calcium concentrations were dose dependently decreased in association with increased calcium phosphate precipitate, crystals and/or microcalculi; magnesium ammonium phosphate crystals and aggregates; and calcium oxalate-containing thin, rod-like crystals. Morphologically, sustained urothelial cytotoxicity and proliferation with a ventral bladder predilection were noted in treated rats by month 1 and urinary carcinomas with a similar distribution occurred by month 9. Urothelial apoptotic rates were unaffected by Muraglitazar treatment or diet. In Muraglitazar-treated rats fed an acidified diet, urine pH was invariably < 6.5, which inhibited formation of calcium-and magnesium-containing solids. Moreover, dietary acidification prevented the urothelial cytotoxic, proliferative, and tumorigenic responses. Collectively, these data support an indirect pharmacologic mode of urinary bladder tumor development involving alterations in urine composition that predispose to urolithiasis and associated decreases in urine-soluble calcium concentrations.
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urothelial carcinogenesis in the urinary bladder of male rats treated with Muraglitazar a pparα γ agonist evidence for urolithiasis as the inciting event in the mode of action
Toxicologic Pathology, 2006Co-Authors: Mark A Dominick, Thomas P Sanderson, Melvin R White, Terry Van Vleet, Samuel M Cohen, Lora L Arnold, M Cano, Sarah H Tannehillgregg, Jeffrey D Moehlenkamp, Crystal R WaitesAbstract:Muraglitazar, a PPARα/γ agonist, dose-dependently increased urinary bladder tumors in male Harlan Sprague–Dawley (HSD) rats administered 5, 30, or 50 mg/kg/day for up to 2 years. To determine the mode of tumor development, male HSD rats were treated daily for up to 21 months at doses of 0, 1, or 50 mg/kg while being fed either a normal or 1% NH4Cl-acidified diet. Muraglitazar-associated, time-dependent changes in urine composition, urothelial mitogenesis and apoptosis, and urothelial morphology were assessed. In control and treated rats fed a normal diet, urine pH was generally ≥6.5, which facilitates formation of calcium- and magnesium-containing solids, particularly in the presence of other prolithogenic changes in rat urine. Urinary citrate, an inhibitor of lithogenesis, and soluble calcium concentrations were dose dependently decreased in association with increased calcium phosphate precipitate, crystals and/or microcalculi; magnesium ammonium phosphate crystals and aggregates; and calcium oxalate-con...
