Pharmacokinetic challenges and novel formulation approaches for enhanced bioavailability of caffeic acid: a review

Caffeic acid (CA), a derivative of hydroxycinnamic acid that is naturally abundant in coffee, fruits, vegetables, and herbal medicines, has attracted significant interest due to its various pharmacological properties, which include antioxidant, anti-inflammatory, antidiabetic, and cardioprotective effects. CA is characterized by relatively low oral bioavailability, primarily resulting from extensive presystemic metabolism occurring in intestinal mucosa and liver, where it undergoes rapid conjugation through glucuronidation, sulfation, and methylation. Its absorption is affected by dietary matrix, composition of gut microbiota, and other co-ingested substances. Once absorbed, CA shows broad distribution across tissues, including potential to penetrate the blood-brain barrier; however, most systemic exposure is due to its metabolites rather than parent compound. Excretion primarily occurs through urine in conjugated forms, and its relatively short half-life restricts prolonged systemic activity. Various approaches, including nanoformulations, lipophilic derivatives, and absorption enhancers, are being explored to address bioavailability issues. A detailed knowledge of CA's pharmacokinetic profile is essential for optimizing its therapeutic potential. Nevertheless, comprehensive studies in humans are still limited, and future research should prioritize standardized pharmacokinetic evaluations, interindividual variability, and dose-response relationships. This review provides a comprehensive summary of the pharmacokinetic properties of CA and highlights existing challenges and prospects for improving its therapeutic application.