Phytochemicals in arthritis management: insight into pharmacodynamic potency with pharmacokinetic profile.

Arthritis, especially osteoarthritis (OA) and rheumatoid arthritis (RA), is a chronic, multifactorial disorder characterized by ongoing inflammation, oxidative stress, immune dysregulation, cartilage degradation and abnormal bone remodeling. These factors significantly contribute to global disability. Traditional treatments, including nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, disease-modifying antirheumatic drugs (DMARDs), and biologics can provide symptomatic relief and immunosuppression. However, their long-term use is often limited due to adverse effects and insufficient structural modification. Recently, plant-derived bioactive compounds have emerged as promising multi-target agents that can influence key pathogenic pathways, including NF-κB, MAPK, JAK/STAT, Nrf2/Keap1, and NLRP3 inflammasome signaling. Compounds such as polyphenols (e.g., curcumin, resveratrol, quercetin, EGCG), terpenoids (e.g., boswellic acids, andrographolide, celastrol), alkaloids (e.g., berberine, sinomenine), flavonoids, and other related phytochemicals exhibit anti-inflammatory, antioxidant, immunomodulatory, chondroprotective, and anti-resorptive effects in preclinical and emerging clinical studies. However, the clinical success of these compounds is often hindered by unfavorable pharmacokinetic profiles, including poor aqueous solubility, limited intestinal permeability, extensive first-pass metabolism, microbiota-driven biotransformation, and rapid renal or biliary elimination. These factors result in low and inconsistent systemic and synovial exposure. This review integrates the pharmacodynamic mechanisms with pharmacokinetic behavior (absorption, distribution, metabolism, and excretion characteristics) to critically assess the therapeutic potential and limitations of plant-derived compounds in managing arthritis. It also highlights advanced formulation strategies, such as nanocarriers, phytosomes, lipid-based systems and prodrug approaches, to enhance bioavailability, tissue targeting, and clinical applicability within precision medicine frameworks.