A study of intestinal absorption of bicyclol in rats: active efflux transport and metabolism as causes of its poor bioavailability

Wei Tan1, Hui Chen1, Jinping Hu1, Yan Li1

1Department of New Drug Development, Institute of Materia Medica, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100050.


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 (50µM) appearance in mesenteric blood (Pblood) was increased 3, 12, 16-fold by 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 by LSN335984 and increased 5 and 1-fold by TAO and CsA. In addition, the metabolized fraction of bicyclol was decreased by 9%, 33%, 36% with inhibitor of P-gp, CYP3A, or P-gp and CYP3A. Moreover, the cumulative amount of bicyclol in mesenteric blood was increased at concentration range 10-100µM of bicyclol in perfusate. The ER (Pappba/Pappab) value of bicyclol in Caco-2 monolayer was significantly deceased by LSN335984 and CsA.
Conclusion. The poor bioavailability of bicyclol was mostly due to the P-gp mediated efflux and metabolism by CYP3A in intestine, while CYP3A was believed to make more contribution than P-gp.

J Pharm Pharm Sci, 11 (3): 97-105, 2008

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