Lack of inhibition of CYP2C8 by saroglitazar magnesium: In vivo assessment using montelukast, rosiglitazone, pioglitazone, repaglinide and paclitaxel as victim drugs in Wistar rats
| Autor: | Prashant Delvadia, Poonam Giri, Namrata Prajapati, Vipul Joshi, Shyamkumar Giri, Pankaj R. Patel, Mukul R. Jain, Nuggehally R. Srinivas, Meera K. Ladani, Nirmal Patel, Lakshmikant Gupta |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Cyclopropanes
Male Paclitaxel Pharmaceutical Science 02 engineering and technology Pharmacology Acetates Sulfides 030226 pharmacology & pharmacy Cytochrome P-450 CYP2C8 Rosiglitazone 03 medical and health sciences 0302 clinical medicine Pharmacokinetics Piperidines medicine Animals Humans Drug Interactions Pyrroles Rats Wistar CYP2C8 IC50 Montelukast Dose-Response Relationship Drug Phenylpropionates Pioglitazone business.industry Saroglitazar 021001 nanoscience & nanotechnology Repaglinide Rats Cytochrome P-450 CYP2C8 Inhibitors Microsomes Liver Quinolines Carbamates 0210 nano-technology business medicine.drug |
| Zdroj: | European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences. 130 |
| ISSN: | 1879-0720 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect