A study of intestinal absorption of bicyclol in rats: active efflux transport and metabolism as causes of its poor bioavailability.
OBJECTIVE
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.
Tan
Wei
W
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.
Chen
Hui
H
Zhao
Jing
J
Hu
Jinping
J
Li
Yan
Y
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001682:Biological Availability; D001693:Biological Transport, Active; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018938:Caco-2 Cells; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D010477:Perfusion; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001713:Biphenyl Compounds; D065692:Cytochrome P-450 CYP3A Inhibitors; C477843:bicyclol; D051544:Cytochrome P-450 CYP3A