<![CDATA[The rising burden of chronic diseases has accelerated the search for phytotherapeutic combinations that offer multi-target pharmacological actions with lower toxicity. While Peperomia pellucida and Phyllanthus niruri are renowned for their individual antioxidant and anti-inflammatory properties, there is a significant gap in understanding their combined pharmacokinetic behavior and molecular interactions. This study aims to evaluate the pharmacological potential of combined P. pellucida and P. niruri extracts through an integrated approach encompassing phytochemical analysis, pharmacokinetic profiling, and protein-target interaction predictions. Bioactive compounds retrieved from the KNaPSacK JAMU database were analyzed using TargetNet and pkCSM to assess ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) characteristics. Concurrently, the Total Phenolic Content (TPC) of various extract combinations was determined experimentally in triplicate using the Folin–Ciocalteu method to quantify phenolic constituents, serving as a literature-based indicator of potential antioxidant activity. A total of twenty-two bioactive compounds were identified, predominantly comprising lignans, flavonoids, and triterpenoids. Pharmacokinetic modeling revealed a favorable predicted pharmacokinetic profile characterized by predicted good oral absorption, effective clearance rates, low hepatotoxicity, and the absence of CYP2D6 enzyme inhibition. In silico analysis indicated binding affinity to oxidoreductase enzymes (CYP1A2, polyphenol oxidase 2), nuclear receptors (estrogen and retinoic acid), and key regulatory enzymes such as COX-2 and PTPN1. Notably, TPC values increased proportionally with the concentration of P. pellucida, peaking at 212.44 ± 1.06 mg GAE/g at a 20:80 ratio (P. niruri:P. pellucida). The integration of experimentally measured TPC and in silico findings suggests that phenolic-rich formulations of this combination may possess a favorable pharmacokinetic profile and the potential to modulate multiple biological targets, supporting their further investigation as multi-target phytopharmaceuticals.]]>
