Preclinical Pharmacokinetics and CYP Modulation Activity of Chebulinic Acid: A Potent Molecule Against Metabolic Disease

Abstract

Background: Chebulinic acid (CA) is an active constituent of Terminalia chebula fruits with therapeutic potential against multiple metabolic diseases, including dementia, benign prostate hyperplasia, and osteoporosis. Objective: The present work intends to explore the preclinical pharmacokinetics, including the absolute bioavailability of CA and its influence on the gene expression of cytochrome P450 enzymes in the liver. Methods: Quantifying CA and probe drugs in vitro samples and preclinical serum samples of male SD rats were performed using LC-MS/MS. The influence of CA on the hepatic CYPs and their gene expression was analyzed in rat liver by quantitative real-time polymerase chain reaction. Results: The plasma protein binding was found to be 84.81 ± 7.70 and 96.34 ± 3.12, blood-to-plasma ratio of 0.62 ± 0.16 and 0.80 ± 0.23 at 1 μM and 10 μM concentrations, respectively. Again, the absolute oral bioavailability of CA at 100 mg/kg was found to be 37.56 ± 7.3%. The in-vivo pharmacokinetic profile of probe drugs revealed CA to have significant inducing effects on CYP1A2, 2C11, 2D2, and 2E1 after 14 days, which correlates to both in-vitro rat microsomal data and gene expression results. Conclusion: Altogether, pharmacokinetic parameters reveal CA to have an affinity to distribute across different extravascular tissues and induce rat liver CYP enzymes.