title: Assessment of dose proportionality of muraglitazar after repeated oral dosing in rats via a sparse sampling methodology.
abstract: Muraglitazar is an alpha/gamma-dual peroxisome proliferator-activated receptor (PPAR) agonist. This study evaluated the single- and multiple-dose oral toxicokinetics of muraglitazar in rats at doses of 3, 30 and 300 mg/kg/day. In total, 15 rats/gender/dose group received muraglitazar every day for 1 month. On both day 1 and day 28, blood samples were obtained at 0.5, 2, 4, 6, 8 and 24 h post-dose, followed by LC/MS analysis. In order to minimize blood loss in the rats, a sparse sampling approach was used to delineate the toxicokinetics. The peak plasma concentration (C(max)) and area under the plasma concentration-time curve (TAUC(0-t)) values for muraglitazar increased in a proportion less than the increment in dose. As the dose increased in the ratio 1:10:100, the C(max) for muraglitazar in male and female rats increased in the ratio of 1:10.3:58.6 and 1:15.3:75.3 on day 1, and 1:5.9:28.1 and 1:13.3:37.3 on day 28, respectively. The corresponding TAUC(0-t) values for males and females were in the ratio of 1:10.2:131 and 1:12.4:131 on day 1, and 1:9.5:93.4 and 1:11.8:94.3 on day 28, respectively. The results indicate that muraglitazar exhibits a dose dependent toxicokinetics in rats and the systemic exposure of muraglitazar was decreased on day 28 compared with day 1.
authors.affiliation: Biotransformation Department, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. ming.yao@bms.com
authors.forename: Ming
authors.initials: M
authors.lastname: Yao
authors.forename: Arun
authors.initials: A
authors.lastname: Swaminathan
authors.forename: Nuggehally
authors.initials: N
authors.lastname: Srinivas
mesh_terms: D000284:Administration, Oral; D000818:Animals; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity; D007004:Hypoglycemic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity; D000960:Hypolipidemic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity; D008297:Male; D010080:Oxazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D010080:Oxazoles; D047493:PPAR alpha; D047495:PPAR gamma; D005998:Glycine; C500085:muraglitazar