Muraglitazar: A dual peroxisome proliferator-activated receptor

CHEMISTRY AND PHARMACOLOGY Muraglitazar is a novel, non-thiazolidinedione PPAR alpha/gamma dual agonist. It is synthesized from oxybenzylglycine and has shown to have high binding affinity to the PPAR alpha and PPAR gamma receptors. When compared with rosiglitazone, muraglitazar was found to have comparable functional activity at PPAR gamma. When compared with fenofibric acid, a weak PPAR alpha agonist, muraglitazar was found to be more potent at PPAR alpha.14 In vivo, muraglitazar has demonstrated glucose and TG-lowering effects in male db/db mice.14 It was also associated with a reduction in both free fatty acid and insulin levels.14 Devasthale et al suggested that effects on glucose and insulin levels are mediated through PPAR gamma while TG-lowering effects are mediated through PPAR alpha.14 The effects of muraglitazar have also been examined in sigma db/db mu mice, which serve as genetic models of diabetes and obesity.17 After 2 weeks of treatment with muraglitazar 10 mg/kg/d, fasting glucose was significantly decreased, as was area under the glucose-response curve following oral glucose challenge.17 In a separate study over 4 weeks, muraglitazar-treated mice showed lower levels of TGs, free fatty acids, glucose, and insulin with doses of 0.1 to 30 mg/kg/d. Treatment with a dose of 30 mg/kg/d was also associated with improved polyuria, as demonstrated by reduced urine output.17 Muraglitazar may also have a possible effect on atherogenesis by enhancing reverse cholesterol transport in THP1 macrophage cells. The agent was also found to inhibit the secretion of MCP1, a chemoattractant protein, which may translate into a reduction in macrophage migration into vessel walls.18 Pharmacokinetics. In male rats, muraglitazar was 88% bioavailable following oral administration of 10 mg/kg. Following intra-arterial administration of 5 mg/kg, T½ was 7.3±4.0 hours with systemic clearance of 3 mL/min·kg.14 The pharmacokinetics of muraglitazar were also evaluated in a placebo-controlled, single-dose study of healthy subjects. Subjects were randomly assigned to receive 1 of 6 doses of muraglitazar (0.5, 1.5, 5, 25, 100, or 300 mg). Muraglitazar was rapidly absorbed with a Tmax of 1 to 6 hours and a mean T½ of 19 to 27 hours.19 The effects of age and gender on the pharmacokinetics of muraglitazar were described in abstract form.20 Eighty subjects were enrolled in 1 of 4 groups: young males or females (aged 18–40 y) or elderly males or females (aged ≥65 y). Subjects received 10 mg of muraglitazar by mouth, and blood samples were collected for 72 hours following the dose. Age appeared to have little effect, as the ratio of the Cmax in elderly patients to that of young patients was 1.097 (90% CI, 1.004–1.199), and the ratio of the AUC (elderly to young) was 1.257 (90% CI, 1.160–1.361). The ratio of the Cmax in women to men was 1.132 (90% CI, 1.036–1.237), and the ratio of the AUC in women to men was 1.086 (90% CI, 1.002–1.176). The authors reported that these factors do not require dose adjustment.20