Wei Tan1, Hui Chen, Jing Zhao, Jinping Hu, Yan Li. 1. Department of New Drug Development, Institute of Materia Medica, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100050, People's republic of China.
Abstract
PURPOSE: To determine the possible mechanism of poor bioavailability of bicyclol, and clarify the respective contribution of P- glycoprotein (P-gp) and Cytochrome 3A (CYP3A). METHODS: Rat in situ single-pass intestinal perfusion and Caco-2 cell monolayer model with selective inhibitors of CYP3A and P-gp were employed. RESULTS: In rat intestinal perfusion, bicyclol (50 microM) appearance in mesenteric blood (Pblood) was increased 3, 12 and 16-fold after addition of inhibitors of P-gp (LSN335984), CYP3A (troleandomycin, TAO) or P-gp and CYP3A (Cyclosporin A, CsA), respectively, whereas permeability of midazolam (CYP3A substrate only) was unchanged after addition of LSN335984 and increased 5 fold after addition of TAO. Moreover, the cumulative amount of bicyclol in mesenteric blood was increased at concentration range 10-100 microM of bicyclol in perfusate. The basolateral to apical permeability value of bicyclol in Caco-2 monolayer was significantly deceased by LSN335984 and CsA. CONCLUSIONS: The poor bioavailability of bicyclol is mostly due to P-gp mediated efflux and metabolism by CYP3A in intestine, with CYP3A making more contribution than P-gp.
PURPOSE: To determine the possible mechanism of poor bioavailability of bicyclol, and clarify the respective contribution of P- glycoprotein (P-gp) and Cytochrome 3A (CYP3A). METHODS:Rat in situ single-pass intestinal perfusion and Caco-2 cell monolayer model with selective inhibitors of CYP3A and P-gp were employed. RESULTS: In rat intestinal perfusion, bicyclol (50 microM) appearance in mesenteric blood (Pblood) was increased 3, 12 and 16-fold after addition of inhibitors of P-gp (LSN335984), CYP3A (troleandomycin, TAO) or P-gp and CYP3A (Cyclosporin A, CsA), respectively, whereas permeability of midazolam (CYP3A substrate only) was unchanged after addition of LSN335984 and increased 5 fold after addition of TAO. Moreover, the cumulative amount of bicyclol in mesenteric blood was increased at concentration range 10-100 microM of bicyclol in perfusate. The basolateral to apical permeability value of bicyclol in Caco-2 monolayer was significantly deceased by LSN335984 and CsA. CONCLUSIONS: The poor bioavailability of bicyclol is mostly due to P-gp mediated efflux and metabolism by CYP3A in intestine, with CYP3A making more contribution than P-gp.