In-vitro and in-vivo pharmacokinetics of IS01957, p-coumaric acid derivative using a validated LC–ESI–MS/MS method in mice plasma

Abstract

Plant derived natural products have been the major source for treatment of diseases traditionally but with the advent of modern systems of medicine, there is need to explore the active constituents present in it followed by modification for better therapeutic activity, low toxicity and favorable pharmacokinetics to become a drug molecule. A simple, rapid and sensitive high-performance liquid chromatography–tandem mass spectrometry (LC–MS/MS) method was developed and validated according to Food and Drug Administration guidelines for determination of IS01957, a derivative of naturally occurring para coumaric acid in mice plasma. The extraction of the analyte and the internal standard (Carbamazepine) from the plasma samples involved protein precipitation using acetonitrile. Results of validation parameters were met with the acceptance criteria of the FDA guidelines. Method was highly sensitive (5 ng/mL) that could determine very low concentration of compound in plasma The developed and validated method was successfully applied to determine compound’s metabolic stability in mouse liver microsomes (MLM) and human liver microsomes (HLM). Test compound was found to be stable in MLM and HLM in the experimental conditions. Metabolic stability data was extrapolated which was further correlated to pharmacokinetics study in mice through oral, intraperitoneal and intravenous administration. In-vitro half life was found to be greater than 2 h in both MLM and HLM. Hepatic extraction ratio of the compound was found to be in the intermediate range. Pharmacokinetic evaluations revealed that it is a suitable candidate for intraperitoneal as well as oral administration.