Identification of permeability-related hurdles in oral delivery of curcumin using the Caco-2 cell model

Curcumin a poly-phenolic compound possesses diverse pharmacologic activities; however, its development as a drug has been severely impeded by extremely poor oral bioavailability. Poor aqueous solubility and extensive metabolism have been implicated for this but the role of membrane permeability has not been investigated. In the present study, permeability of curcumin was assessed using the Caco-2 cell line. Curcumin was poorly permeable with a P(app) (A → B) value of 2.93 ± 0.94 × 10(-6)cm/s. P(app) value in (B → A) study was found out to be 2.55 ± 0.02 × 10(-6)cm/s, thus ruling out the role of efflux pathways in poor oral bioavailability of curcumin. Studies using verapamil, a P-gp inhibitor, further confirmed this finding. Detailed mass balance studies showed loss of curcumin during transport. Further experiments using lysed cells revealed that 11.78% of curcumin was metabolized during transport. Studies using itraconazole, a CYP3A4 inhibitor, established its role in curcumin metabolism. Curcumin was also found to accumulate in cells as revealed by CLSM studies. Sorption and desorption kinetic studies further confirmed accumulation of curcumin inside the cells. Amount accumulated was quantitated by HPLC and found to be >20%. Thus, intestinal first-pass metabolism and intracellular accumulation played a role in poor permeability of curcumin. Based on its poor aqueous solubility and intestinal permeability, curcumin can be classified as a BCS Class IV molecule. This information can facilitate designing of drug delivery systems for enhancement of oral bioavailability of curcumin.