Lack of the cytochrome P450 3A interaction of methanolic extract of Withania somnifera, Withaferin A, Withanolide A and Withanoside IV

Abstract

Aims: Withania somnifera is widely employed as a rejuvenator and expected to
promote physical health and increase longevity. The aim of the present research work
was to evaluate Cytochrome P450 3A (CYP3A) interaction of Withania somnifera.
Materials and Methods: In vitro CYP3A interaction of methanolic extract of
Withania somnifera (WS) and its principal phytoconstituents: Withaferin–A (WA),
Withanolide–A (WL‑A) and Withanoside–IV (WS‑IV) were investigated in rat
and human liver microsomes. In vivo CYP3A interaction potential was investigated
by administering methanolic extract of WS orally at a dose of 500 mg/kg in female
Wistar rats. Sildenafil citrate was used to index the activity of CYP3A. Results: IC50
values of methanolic extract of Withania somnifera, WA, WL‑A, WS‑IV were found
to be 200 µg/ml, >20 µM, >64 µM and >64 µM for CYP3A both in rats and humans,
respectively. When sildenafil citrate was orally co‑administered with methanolic
extract of WS and compared with orally administered sildenafil citrate alone, the
area under plasma concentration time (AUC) curve and Cmax did not significantly
differ as compared to the group which received rifampicin orally (positive control).
Conclusions: Results suggested that methanolic extract of WS, WA, WL‑A, WS‑IV
showed no in vitro CYP3A inhibition in rats and humans. Methanolic extract of WS
did not significantly alter the pharmacokinetics of sildenafil citrate in rats; indicating
its safety when co‑administered with other drugs that are substrates of CYP3A. Thus
the results indicate the lesser likelihood of drug herb interactions when concomitantly
administered with CYP3A substrates.