Pharmacokinetics and bioequivalence of Withania somnifera (Ashwagandha) extracts - A double blind, crossover study in healthy adults.

ABSTRACT

Introduction: Withania somnifera (WS) or ashwagandha is an adaptogenic plant used extensively in traditional medicines and as a food supplement. Despite a long history of use and numerous clinical trials, the human pharmacokinetics of withanolides, the active phytochemicals in WS extracts, have not been fully evaluated. This study evaluated the oral pharmacokinetics and bioequivalence of active withanolides in human plasma after administration of a single dose of two commercial ashwagandha extracts containing equal amounts of total withanolides. Methods: This randomized, double-blind, single-dose crossover study of 16 healthy human volunteers evaluated the acute oral bioavailability of withanolides and the bioequivalence of two WS extracts, WS-35 and WS-2.5. WS-35 was standardized to total withanolides not less than 40% comprising not less than 35% withanolide glycosides and WS-2.5 was standardized to 2.5% withanolides. The clinical dosages were normalized to 185 mg of total withanolide in each extract at the bioequivalent dosages. The pharmacokinetic parameters of withanolide A, withanoside IV, withaferin A, and total withanolides were quantified in the blood plasma using a validated LC-MS/MS method. Results: The half-life, C-max, and mean residence time of the total withanolides were 5.18, 5.62 and 4.13 times significantly higher and had lower systemic clearance with WS-35 than with WS-2.5 extract. Considering the plasma AUC 0-inf of total withanolides per mg of each WS extract administered orally, WS-35 was 280.74 times more bioavailable than WS-2.5. Conclusion: The results of this study highlight the importance of withanolide glycosides in improving the pharmacokinetics of WS extracts. Owing to its superior pharmacokinetic profile, WS-35, with 35% withanolide glycosides, is a promising candidate for further studies on Withania somnifera. Clinical trial registration CTRI/2020/10/028397 [registered on13/10/2020] (Trial prospectively registered) http//ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=42149&EncHid=&userName=CTRI/2020/10/028397.