Clinical pharmacokinetics and pharmacometabolomics of Andrographis paniculata capsules: Bridging drug disposition and metabolic response to precision medicine.

Andrographis paniculata (Burm. F.) Nees (AP) is a phytomedicinal plant traditionally used for colds, infections, and diabetes in Southeast Asia. The bioactive diterpenoids such as andrographolide, 14-deoxyandrographolide, and neoandrographolide has anti-inflammatory, antimicrobial, and glucose-lowering effects. Although widely used, clinical studies integrating AP's drug composition with its pharmacometabolomics responses remain limited. This study integrated pharmacokinetics (PK) and pharmacometabolomics (PMx) to understand dose-response relationships and pharmacological effects of orally administered AP capsules (1000 mg and 2000 mg) to 12 healthy volunteers under fasting conditions. Three biomarkers were measured from five AP brands to determine the highest-concentration AP capsule for dosing. PK analysis used 75 plasma samples while PMx analysis involved 96 plasma and urine samples. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) were used for both analyses. Statistical analysis included multivariate analyses (PCA, PLS-DA), followed by peaks-to-pathway analysis via MetaboAnalyst 5.0. Time to reach maximum plasma concentration (Tmax) for andrographolide, 14-deoxyandrographolide, and neoandrographolide was 1.5 h, with maximum plasma concentration (Cmax) of 10.15 ng mL^-1, 7.02 ng mL^-1 and 58.45 ng mL^-1, respectively. At 1000 mg, AP enhanced steroid hormone biosynthesis, while 2000 mg induced broader metabolic shifts, enriching pathways such as biosynthesis of unsaturated fatty acids, alanine/aspartate/glutamate metabolism, and lysine degradation. No free bioactive compounds were detected in urine, indicating metabolism into conjugated forms. Clinical PK guided PMx revealed metabolic responses supporting AP's potential as a therapeutic agent for inflammation and glucose lowering effect. Further clinical research could optimize dosing and advance AP as a precision medicine candidate.