Title:Preclinical Pharmacokinetics and CYP Modulation Activity of Chebulinic Acid: A
Potent Molecule Against Metabolic Disease
Volume: 24
Issue: 8
Author(s): Arpon Biswas, Sarvesh Kumar Verma, Shiv Kumar, Tripti Mishra, Mukesh Kumar, Abhijit Deb Choudhury, Sristi Agrawal, Sachin Nashik Sanap, Amol Chhatrapati Bisen, Anjali Mishra, Tadigoppula Narender and Rabi Sankar Bhatta*
Affiliation:
- Pharmaceutics and Pharmacokinetic Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India
Keywords:
Natural product, pharmacokinetics, bioavailability, chebulinic acid, CYP enzyme, LC-MS/MS.
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.
