An Integrated in Silico-In Vitro-In Vivo Approach for Pharmacokinetic Studies of Andrographolide Using Aqueous Extract of Andrographis Paniculata (Burm.F.) Wall. Ex Nees

Andrographis paniculata is a herbal plant that has been used traditionally for decades to treat a wide range of diseases. To this date, no research on the integration of in silico, in vitro, and in vivo pharmacokinetics (PK) has been documented on andrographolide (AG), the primary bioactive compound in A. paniculata. In this study, we employed an in silico approach to predict the physicochemical properties, metabolism, and toxicity of AG. PK properties were validated using in vitro assays and further tested in Wistar rats. Based on in silico prediction, AG demonstrated to be a soluble, permeant, and lipophilic drug. AG was regarded as a non-mutagenic and non-carcinogenic drug with a low risk of oral absorption. In vitro assays showed that AG was stable at all pH levels tested, had a high equilibrium solubility and moderately stable in the mouse plasma. AG was also permeant across the Caco-2 monolayer with Papp values of 9.627 × 10−6 cm/s (apical) and 18.1 × 10−6 cm/s (basolateral). It had a stable metabolism in the liver microsomes and did not have any inhibitory effects on the enzymes CYP2C8, CYP2C19, CYP2D6, or CYP3A4 (MDZ). Based on in vivo results, the volume of distribution and clearance were both high, with a short elimination half-life (0.17 ± 0.0 h) contributing to the low oral bioavailability (~2%). Rapid oral absorption was shown with Tmax of 0.25 h. Our data revealed promising drug-like properties of AG, and its pharmacokinetics profiles support its potential in developing andrographolide-based products from natural resources.