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Assessment of dose proportionality of muraglitazar after repeated oral dosing in rats via a sparse sampling

Ming Yao1, Arun Swaminathan, Nuggehally Srinivas

  • 1Biotransformation Department, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. ming.yao@bms.com

Biopharmaceutics & Drug Disposition
|November 23, 2006
PubMed

Insights

Muraglitazar, a dual PPAR agonist, shows dose-dependent toxicokinetics in rats. Systemic exposure decreased after 28 days compared to single-dose administration.

Area of Science:

  • Pharmacology
  • Toxicology
  • Drug Metabolism

Background:

  • Muraglitazar is an alpha/gamma-dual peroxisome proliferator-activated receptor (PPAR) agonist.
  • Understanding the toxicokinetics of drug candidates is crucial for safety assessment.

Purpose of the Study:

  • To evaluate the single- and multiple-dose oral toxicokinetics of muraglitazar in rats.
  • To assess dose-dependent exposure and changes in toxicokinetics over a 28-day period.

Main Methods:

  • Rats received daily oral doses of muraglitazar (3, 30, 300 mg/kg/day) for one month.
  • Sparse blood sampling was performed on days 1 and 28 post-dose (0.5–24 h).
  • Plasma concentrations were analyzed using Liquid Chromatography/Mass Spectrometry (LC/MS).

Main Results:

  • Muraglitazar exhibited dose-dependent toxicokinetics in both male and female rats.
  • Peak plasma concentration (Cmax) and area under the curve (AUC) increased disproportionately to the dose.
  • Systemic exposure (AUC) was lower on day 28 compared to day 1 across all dose groups.

Conclusions:

  • Muraglitazar demonstrates dose-dependent toxicokinetics in rats.
  • Repeated dosing for 28 days resulted in decreased systemic exposure compared to single-dose administration.

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