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

Authors

  • Wei Tan Department of New Drug Development, Institute of Materia Medica, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100050.
  • Hui Chen Department of New Drug Development, Institute of Materia Medica, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100050.
  • Jinping Hu Department of New Drug Development, Institute of Materia Medica, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100050.
  • Yan Li Department of New Drug Development, Institute of Materia Medica, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100050.

DOI:

https://doi.org/10.18433/J3B88V

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 (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.

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Author Biography

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

correspondence author; the head of new drug development ;(professor)

Published

2008-09-06

How to Cite

Tan, W., Chen, H., Hu, J., & Li, Y. (2008). A study of intestinal absorption of bicyclol in rats: active efflux transport and metabolism as causes of its poor bioavailability. Journal of Pharmacy & Pharmaceutical Sciences, 11(3), 97–105. https://doi.org/10.18433/J3B88V

Issue

Section

Pharmaceutical Sciences; Original Research Articles