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Cited by 24Phytochemicals and Medicinal PlantsAnalytical Methods in PharmaceuticalsProtein Interaction Studies and Fluorescence Analysis

Elucidation of plasma protein binding, blood partitioning, permeability, CYP phenotyping and CYP inhibition studies of Withanone using validated UPLC method: An active constituent of neuroprotective herb Ashwagandha

Singh, Sandeep K., Valicherla, Guru R., Bikkasani, Anil K., Cheruvu, Srikanth H., Hossain, Zakir, Taneja, Isha, Ahmad, Hafsa, Raju, Kanumuri S.R. +5 more·2021·Journal of Ethnopharmacology
DOI 10.1016/j.jep.2021.113819
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Abstract

Ethnopharmacological relevance Withanone (WN), an active constituent of Withania somnifera commonly called Ashwagandha has remarkable pharmacological responses along with neurological activities. However, for a better understanding of the pharmacokinetic and pharmacodynamic behavior of WN, a comprehensive in-vitro ADME (absorption, distribution, metabolism, and excretion) studies are necessary.Aim of the study A precise, accurate, and sensitive reverse-phase ultra-performance liquid chromatographic method of WN was developed and validated in rat plasma for the first time. The developed method was successfully applied to the in-vitro ADME investigation of WN.Material and methods The passive permeability of WN was assayed using PAMPA plates and the plasma protein binding (PPB) was performed using the equilibrium dialysis method. Pooled liver microsomes of rat (RLM) and human (HLM) were used for the microsomal stability, CYP phenotyping, and inhibition studies. CYP phenotyping was evaluated using the specific inhibitors. CYP inhibition study was performed using specific probe substrates along with WN or specific inhibitors.Results WN was found to be stable in the simulated gastric and intestinal environment and has a high passive permeability at pH 4.0 and 7.0 in PAMPA assay. The PPB of WN at 5 and 20 μg/mL concentrations were found to be high i.e. 82.01 ± 1.44 and 88.02 ± 1.15%, respectively. The in vitro half-life of WN in RLM and HLM was found to be 59.63 ± 2.50 and 68.42 ± 2.19 min, respectively. CYP phenotyping results showed that WN was extensively metabolized by CYP 3A4 and1A2 enzymes in RLM and HLM. However, the results of CYP Inhibition studies showed that none of the CYP isoenzymes were potentially inhibited by WN in RLM and HLM.Conclusion The in vitro results of pH-dependent stability, plasma stability, permeability, PPB, blood partitioning, microsomal stability, CYP phenotyping, and CYP inhibition studies demonstrated that WN could be a better phytochemical for neurological disorders.

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Authors
Singh, S. K., Valicherla, G. R., Bikkasani, A. K., Cheruvu, S. H., Hossain, Z., Taneja, I., Ahmad, H., Raju, K. S. R., Sangwan, N. S., Singh, S. K., Dwivedi, A. K., Wahajuddin, M., & Gayen, J. R.
Affiliations
  • Central Drug Research Institute (IN)
  • National Institute of Pharmaceutical Education and Research (IN)
  • Central Institute of Medicinal and Aromatic Plants (IN)
Corresponding author
Gayen, Jiaur R.
ORCID
Venue
Journal of Ethnopharmacology
Publisher
Elsevier BV
Published
2021-04
Volume
270
Pages
113819
ISSN
0378-8741 (ISSN-L)
DOI
10.1016/j.jep.2021.113819
OpenAlex
W3121669307
Cited by
24
References
51
Citations by year
2026: 1 · 2025: 5 · 2024: 7 · 2023: 4 · 2022: 5 · 2021: 2
FWCI
5.06
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Journal of Ethnopharmacology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Complementary and alternative medicine › Phytochemicals and Medicinal Plants
  • Physical Sciences › Chemistry › Analytical Chemistry › Analytical Methods in Pharmaceuticals
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Interaction Studies and Fluorescence Analysis
Keywords
Withania somnifera, plasma protein binding, passive permeability, cytochrome P450 inhibition, microsomal stability, pH-dependent stability, UPLC method validation
MeSH terms
Animals, Blood Proteins, Chromatography, High Pressure Liquid, Cytochrome P-450 Enzyme System, Humans, Isoenzymes, Male, Microsomes, Liver, Permeability, Plant Extracts, Protein Binding, Rats, Sprague-Dawley, Neuroprotective Agents, Withania, Rats, Withanolides, Cytochrome P-450 Enzyme Inhibitors

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