Preclinical pharmacokinetics, absolute bioavailability and dose proportionality evaluation of bioactive phytochemical Withanone in rats.
Singh, S.K. Rashid, M. Chaturvedi, S. Agarwal, A. Chauhan, D. Gayen, J.R.
Singh, S.K.
Rashid, M.
Chaturvedi, S.
Agarwal, A.
Chauhan, D.
Gayen, J.R.
Publication Date
2025-01-09
End of Embargo
Supervisor
Rights
© 2025 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Peer-Reviewed
Yes
Open Access status
openAccess
Accepted for publication
2025-01-02
Institution
Department
Awarded
Embargo end date
Collections
Additional title
Abstract
Withanone (WN), a bioactive phytochemical isolated from the medicinal herb Withania somnifera, has shown multiple pharmacological and therapeutic successes, including neuroprotective and anti-cancer activities. However, detailed pharmacokinetic (PK) properties of pure WN were not well defined. Pharmacokinetic (PK) characteristics, dose proportionality, and absolute bioavailability of pure WN were explored in rats using an efficient, reliable, and sensitive LC-MS/MS assay to address this gap. The method shows excellent linearity over 0.5-500 ng/mL (r2 ≥ 0.99), is accurate, and requires less analysis time. A dose proportionality and absolute bioavailability of pure WN were determined in Sprague-Dawley (SD) rats through three ascending oral (10, 20, and 40 mg/kg) and single intravenous (5 mg/kg) PK studies. The peak concentration (Cmax) of WN was 60.53 ± 20.33, 116.30 ± 16.89, and 91.62 ± 6.20 ng/mL, corresponding to oral dosage of 10, 20, and 40 mg/kg, respectively. WN shows poor systemic exposure upon oral administration, leading to low oral bioavailability (<15 %). Additionally, the dose proportionality studies of WN revealed its saturable bioavailability and non-proportional systemic exposure over the dosage range of 10-40 mg/kg in rats. The obtained PK findings of this study would be valuable for better understanding the pharmacological effects of WN, dose regimen optimization for future studies, and relevance for clinical reference to support its future development as a potential therapeutic molecule.
Version
Published version
Citation
Singh SK; Rashid M; Chaturvedi S; Agarwal A; Chauhan D; Gayen JR; Wahajuddin M (2025) 'Preclinical pharmacokinetics, absolute bioavailability and dose proportionality evaluation of bioactive phytochemical Withanone in rats'. Bioorganic Chemistry, . [Link] [DOI]
Link to publisher’s version
Link to published version
Link to Version of Record
Type
Article