Disease relevance of Muraglitazar

• At week 50, heart failure was reported in seven patients (five with muraglitazar and two with pioglitazone), and seven deaths occurred: three from sudden death, two from cerebrovascular accident, and one from pancreatic cancer in the muraglitazar group and one from perforated duodenal ulcer in the pioglitazone group [1].
• OBJECTIVE: We sought to evaluate the effects of muraglitazar, a dual (alpha/gamma) peroxisome proliferator-activated receptor (PPAR) activator within the new glitazar class, on hyperglycemia and lipid abnormalities [1].
• 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 [2].
• 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 [3].
• Muraglitazar: an agent for the treatment of type 2 diabetes and associated dyslipidemia [4].

High impact information on Muraglitazar

• Muraglitazar, a novel dual (alpha/gamma) peroxisome proliferator-activated receptor activator, improves diabetes and other metabolic abnormalities and preserves beta-cell function in db/db mice [5].
• In db/db mice and normal mice, muraglitazar treatment modulates the expression of PPAR target genes in white adipose tissue and liver [5].
• In young hyperglycemic db/db mice, muraglitazar treatment (0.03-50 mg . kg(-1) . day(-1) for 2 weeks) results in dose-dependent reductions of glucose, insulin, triglycerides, free fatty acids, and cholesterol [5].
• The Dual Peroxisome Proliferator-Activated Receptor {alpha}/{gamma} Activator Muraglitazar Prevents the Natural Progression of Diabetes in db/db Mice [6].
• Thus, muraglitazar treatment decreased both insulin resistance and preserved beta-cell function [6].

Biological context of Muraglitazar

• The human major primary metabolic pathways of muraglitazar include acylglucuronidation, aliphatic/aryl hydroxylation, and O-demethylation [7].
• 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 [8].
• In contrast, fecal samples only contained muraglitazar and its oxidative metabolites, suggesting hydrolysis of biliary glucuronides in the intestine before fecal excretion [9].
• Muraglitazar-associated, time-dependent changes in urine composition, urothelial mitogenesis and apoptosis, and urothelial morphology were assessed [3].
• This study evaluated the single- and multiple-dose oral toxicokinetics of muraglitazar in rats at doses of 3, 30 and 300 mg/kg/day [10].

Anatomical context of Muraglitazar

• The parent compound was a minor component in urine, bile, and feces, indicating that muraglitazar was extensively metabolized in mice [8].
• 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 [7].

Associations of Muraglitazar with other chemical compounds

• Muraglitazar (Pargluva), a dual alpha/gamma peroxisome proliferator-activated receptor activator, has both glucose- and lipid-lowering effects in animal models and in patients with diabetes [7].
• In conclusion, muraglitazar was rapidly absorbed, extensively metabolized through glucuronidation and oxidation, and mainly eliminated in the feces via biliary excretion of glucuronide metabolites in all species studied [11].
• Major biotransformation pathways of muraglitazar in mice included taurine conjugate formation, acyl glucuronidation, hydroxylation, and O-dealkylation [8].
• Detection of muraglitazar and trazodone was by positive ion turbo-ion spray mass spectrometry in the SIM mode [12].
• RESULTS: In the muraglitazar-treated patients, death, MI, or stroke occurred in 35 of 2374 (1.47%) patients compared with 9 of 1351 (0.67%) patients in the combined placebo and pioglitazone treatment groups (controls) (relative risk [RR], 2.23; 95% confidence interval [CI], 1.07-4.66; P = .03) [13].

Gene context of Muraglitazar

• The new generation of dual-action PPARs--the glitazars, which target PPAR-gamma and PPAR-alpha (like muraglitazar and tesaglitazar) are on deck in late-stage clinical trials and may be effective in reducing cardiovascular risk, but their long-term clinical effects are still unknown [14].
• This study describes the identification of human cytochrome P450 (P450) and UDP-glucuronosyltransferase (UGT) enzymes involved in the in vitro metabolism of muraglitazar [7].
• Involvement of Multiple Cytochrome P450 and UDP-Glucuronosyltransferase Enzymes in the in Vitro Metabolism of Muraglitazar [7].

Analytical, diagnostic and therapeutic context of Muraglitazar

• Structural elucidation of human oxidative metabolites of muraglitazar: use of microbial bioreactors in the biosynthesis of metabolite standards [2].
• Plasma, urine, and feces were collected from six healthy subjects following oral administration of 14C-labeled muraglitazar (10 mg, 100 microCi) and pooled samples were analyzed [2].

References