Lack of inhibition of CYP2C8 by saroglitazar magnesium: In vivo assessment using montelukast, rosiglitazone, pioglitazone, repaglinide and paclitaxel as victim drugs in Wistar rats

Eur J Pharm Sci. 2019 Mar 15:130:107-113. doi: 10.1016/j.ejps.2019.01.005. Epub 2019 Jan 8.

Abstract

Saroglitazar, a PPAR αҮ agonist, is currently undergoing global development for the treatment of NASH and other indications. Saroglitazar showed CYP2C8 inhibition in human liver microsomes (IC50: 2.9 μM). The aim was to carry out drug-drug interaction (DDI) studies in Wistar rats using saroglitazar (perpetrator drug) with five CYP2C8 substrates. Also, the in vitro CYP2C8 inhibitory potential of saroglitazar in rat liver microsomes (RLM) was evaluated to justify use of preclinical model. The oral pharmacokinetics of various CYP2C8 substrates; montelukast, rosiglitazone, pioglitazone, repaglinide and intravenous pharmacokinetics of paclitaxel was assessed in the presence/absence of oral saroglitazar (4 mg/kg) in Wistar rats. A separate study was performed to assess the oral pharmacokinetics of saroglitazar. Serial blood samples were collected from all studies and the harvested plasma were stored frozen until bioanalysis. LC-MS/MS was used for the analysis of various analytes; concentration data was subjected to noncompartmental pharmacokinetic analysis. Statistical tests (unpaired t-test) were employed to judge the level of DDI. Generally, the pharmacokinetics of CYP2C8 substrates was not affected by the concomitant intake of saroglitazar as judged by the overall exposure (AUC0-last and AUC0-inf) and elimination half-life. The CYP2C8 IC50 of 4.5 μM in RLM for saroglitazar, supported the use of rats for this DDI study. In conclusion, pharmacokinetic data of diverse CYP2C8 substrates suggested that coadministration of saroglitazar did not cause clinically relevant DDI.

Keywords: CYP2C8 inhibition; Clinically relevant DDI; Coadministration; Drug-drug interaction; LC-MS/MS; PPAR αҮ agonist; Rat liver microsomes.

MeSH terms

  • Acetates / pharmacokinetics
  • Animals
  • Carbamates / pharmacokinetics
  • Cyclopropanes
  • Cytochrome P-450 CYP2C8 / metabolism*
  • Cytochrome P-450 CYP2C8 Inhibitors / pharmacokinetics*
  • Dose-Response Relationship, Drug
  • Drug Interactions / physiology
  • Humans
  • Male
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism*
  • Paclitaxel / pharmacokinetics
  • Phenylpropionates / pharmacokinetics*
  • Pioglitazone / pharmacokinetics
  • Piperidines / pharmacokinetics
  • Pyrroles / pharmacokinetics*
  • Quinolines / pharmacokinetics
  • Rats
  • Rats, Wistar
  • Rosiglitazone / pharmacokinetics
  • Sulfides

Substances

  • Acetates
  • Carbamates
  • Cyclopropanes
  • Cytochrome P-450 CYP2C8 Inhibitors
  • Phenylpropionates
  • Piperidines
  • Pyrroles
  • Quinolines
  • Sulfides
  • Rosiglitazone
  • repaglinide
  • saroglitazar
  • Cytochrome P-450 CYP2C8
  • montelukast
  • Paclitaxel
  • Pioglitazone