Determination of permeability, plasma protein binding, blood partitioning, pharmacokinetics and tissue distribution of Withanolide A in rats: A neuroprotective steroidal lactone

Abstract

Preclinical Research & Development Withanolide A (WA), a steroidal lactone is a major bioactive constituent of Withania somnifera (L.) with remarkable neuropharmacological activity. In this study, we investigated the permeability, plasma protein binding (PPB), blood partitioning, intravenous (i.v.), and oral pharmacokinetics as well as i.v. tissue distribution (TD) of pure WA in a rat model. The PPB, RBCs partitioning, and permeability of WA were determined by Ultra Performance Liquid Chromatography (UPLC) method. However, the pharmacokinetics and TD of WA were evaluated by validated and sensitive liquid chromatography coupled mass spectrometry (LC‐ESI‐MS/MS) method. The PPB and permeability of WA were determined by equilibrium dialysis and parallel artificial membrane permeability assay method, respectively. The results demonstrated that WA has high PPB and passive permeability. Furthermore, WA was found to have fast equilibration between RBCs and plasma. Following i.v. (2 mg/kg) and per‐oral (25 mg/kg) administration of WA, the max concentration (Cmax) in plasma was found as 85.53 ± 6.54 and 48.04 ±5.78 ng/mL, respectively. The TD study results indicated that WA has a rapid and wide TD. The maximum concentration in various tissues was found in following order: Clung > Cliver > Ckidney ≈ Cspleen > Cheart > Cbrain. The preclinical in vitro, as well as pharmacokinetics and TD results, are anticipated to support the future preclinical and clinical application of WA.

Leishmanicidal Activity of Withanolides from Aureliana fasciculata var. fasciculata

“…The low VDss might suggest plasma protein binding (PPB) and this phenomenon influences the absorption, biodistribution, metabolism, and excretion of drugs. In silico results of our study also corroborate with the one performed by Singh et al [43] in which withanolide A from Withania somnifera (L.), with neuropharmacological activity, presented high PPB, passive permeability and a fast and wide distribution kinetics in vitro. Also, Dubay et al [44] demonstrated that withanolides and withanosides of W. somnifera have a strong binding to serum albumin.…”

Effects of Withania somnifera (Ashwagandha) on Stress and the Stress- Related Neuropsychiatric Disorders Anxiety, Depression, and Insomnia

“…Plasma bioavailability of withaferin A was also shown in rats after oral administration of a polyherbal formulation containing WS root [ 147 ]. Plasma PK of withanolide A was established in rats following oral administration of the compound, which also showed wide tissue distribution; notably, brain levels were considerably lower than in lung, kidney, liver, heart, and spleen [ 148 ]. Four major withanamides were detected in the mouse brain following the intraperitoneal administration of an extract of WS [ 149 ].…”

Withanolides from the genus Physalis: a review on their phytochemical and pharmacological aspects

“…In addition, the pharmacokinetic data of withanolides should be taken seriously. Recently, several pharmacokinetic studies of individual withanolides have been reported, which demonstrated that the low bioavailability of this type of bioactive molecules limited their clinical application. Employing the Madin‑Darby canine kidney cell culture system, the absorption characteristics of several withanolides have been investigated, and different results have been observed.…”

“…In this study, withanolides were diluted in Hank's buffered saline and tested for permeability by the SinoVeda's cell culture system; withanone, 1,2‐deoxywithastramonolide, and withanolides A and B were highly permeable; withanosides IV–V were low permeable; however, withaferin A ( 13 ) was either impermeable or metabolized on passing through the cell layer . Furthermore, the pharmacokinetic profiles of withanolide A were also assessed using Sprague Dawley rats; very low concentration in plasma and poor bioavailability in orally administered rat have been found . It is reported that 13 could be rapidly removed either in male rat or in human liver microsomes after oral administration; the first‐pass metabolism of 13 may be a major obstacle to good oral bioavailability in male rats and humans .…”