Quantitative evaluation of the function of small intestinal P-glycoprotein: comparative studies between in situ and in vitro.
OBJECTIVE
The extent of intestinal absorption of MDR1 P-glycoprotein (P-gp) substrate drugs may be affected by interindividual differences in the expression level of P-gp, and/or by simultaneously administered P-gp substrates/inhibitors. The purpose of the present study is to examine whether the extent to which the intestinal absorption is affected by P-gp can be predicted from in vitro experiments.


METHODS
The in situ intestinal perfusion experiments were performed for 12 compounds in mdrla/lb (-/-) and normal mice to determine the permeability-surface area (PS) product. Thus determined intestinal P-gp function was compared with the in vitro P-gp function, which was determined by comparing the transcellular transport across human P-gp expressing and parental LLC-PK1 monolayers.


RESULTS
In situ experimental results revealed that the extent to which the intestinal absorption is affected by P-gp was in the following order: quinidine > ritonavir > loperamide, verapamil, daunomycin > digoxin, cyclosporin A > dexamethasone, and vinblastine. A significant correlation was observed between P-gp function determined in the intestinal perfusion and that in LLC-PKI monolayers.


CONCLUSIONS
The in vitro transcellular transport across P-gp expressing monolayers may be used to predict the extent to which the intestinal absorption is affected by P-gp.
Adachi
Yasuhisa
Y
School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Suzuki
Hiroshi
H
Sugiyama
Yuichi
Y
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001812:Blood-Brain Barrier / Q000378:metabolism; D066298:In Vitro Techniques; D007408:Intestinal Absorption / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D007583:Jejunum / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism*; D010599:Pharmacokinetics; D013997:Time Factors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004364:Pharmaceutical Preparations