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Xenobiotica
the fate of foreign compounds in biological systems
Volume 48, 2018 - Issue 12
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Animal Pharmacokinetics and Metabolism

Preclinical evaluation of saroglitazar magnesium, a dual PPAR-α/γ agonist for treatment of dyslipidemia and metabolic disorders

, , , , , , , , , & show all
Pages 1268-1277 | Received 18 Oct 2017, Accepted 01 Dec 2017, Published online: 22 Dec 2017
 

Abstract

1. Saroglitazar, a novel peroxisome proliferator-activated receptor (PPAR) agonist, regulates lipid and glucose metabolism. The objective of this report is to provide a preclinical evaluation (in vitro/in vivo) of ADME properties of saroglitazar. In vitro studies included determination of permeability, metabolic stability, plasma protein binding, CYP reaction phenotyping and CYP inhibitory liability. In vivo studies included oral bioavailability and pharmacokinetic assessment in mouse, rat and dog. The excretion of saroglitazar was determined in rats. Exploratory metabolism of saroglitazar was evaluated using in vitro and in vivo samples.

2. Saroglitazar was metabolically more stable in human liver microsomes as compared to rat and dog liver microsomes, highly protein bound (98–99.6%) with high Caco2 permeability (104 nm/s) with <2 efflux ratio. In vitro metabolism in rat, dog and human liver microsomes revealed three putative metabolites corresponding to di-hydroxylation, mono-oxygenation and dehydrogenation moieties.

3. Oral bioavailability was 100%, 72% and 47% in mouse, rat and dog, respectively. The intravenous clearance and volume of distribution of saroglitazar were 3.6, 8.5 and 6.9 mL/min/kg and 1.3, 4.8 and 1.8 L/kg for mouse, rat and dog, respectively. The elimination half-life of saroglitazar ranged between 6 and 15 h. Saroglitazar appeared to be eliminated via hepatobiliary route with negligible renal excretion.

Declaration of interest

All the authors are employees of Cadila Healthcare Limited (CHL) and have no conflict of interest on content of research work (ZRC communication no. 560). The presented research work has been funded by CHL, no external funding was received for this work.

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