A mechanistic investigation of the bioavailability enhancing potential of lysergol, a novel bioenhancer, using curcumin

Abstract

Lysergol (LYZ), a novel bioenhancer, has shown potential to enhance the bioavailability of some antibiotics. In the present investigation, the bioavailability enhancing potential of LYZ on curcumin (CUR) has been explored. We initially carried out in vivo pharmacokinetic and in situ permeation studies of CUR with and without LYZ coadministration. In presence of LYZ, the C_max, AUC and elimination half-life of CUR were significantly increased. A noteworthy decrease in the clearance of CUR was also observed. An enhancement (3.3-fold) in the effective permeability of CUR was observed. To delve into the mechanistic insights, the probable role of LYZ in inhibiting the metabolism of CUR was investigated. In vitro phase I and II metabolic stability studies of CUR following pre-incubation with LYZ using rat liver microsomes were performed. Also, its effect on major efflux transporters using human P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) membrane preparations was examined. The corroboration of results was provided by in situ permeation and in vivo pharmacokinetic study of digoxin (probe P-gp substrate) and sulfasalazine (probe BCRP substrate) in the presence and absence of LYZ. The results were compared with the inhibitory potential of verapamil (for P-gp) and pantoprazole (for BCRP). Furthermore, the studies ruled out the probability of P-gp inhibition but strongly evidenced the involvement of BCRP inhibition. A remarkable increase in in vitro half-life of CUR and 1.4-fold enhancement in intestinal permeation of sulfasalazine in presence of LYZ clearly revealed that bioavailability enhancing potential is attributed to the inhibition of metabolic enzymes and BCRP efflux transporters.