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Assessment of dose proportionality of muraglitazar after repeated oral dosing in rats via a sparse sampling methodology
Author(s) -
Yao Ming,
Swaminathan Arun,
Srinivas Nuggehally
Publication year - 2007
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.528
Subject(s) - toxicokinetics , chemistry , chromatography , zoology , dosing , pharmacokinetics , medicine , biology
Muraglitazar is an α / γ ‐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. Copyright © 2006 John Wiley & Sons, Ltd.