Effects of lipopolysaccharide on intestinal P-glycoprotein expression and activity.
It is well known that pharmacokinetics is often altered by changing the expression and activity of P-glycoprotein during sepsis. However, there have been few reports about expression and activity of P-glycoprotein in the small intestine during sepsis. We examined the levels of intestinal P-glycoprotein expression and activity using a rat sepsis model induced by lipopolysaccharide (LPS, from Escherichia coli). LPS was administered to male Wistar/ST rats intraperitonealy (i.p.) at 5 mg/kg. The small intestine was excised before and 1, 3 and 7 days after LPS administration, and the intestinal P-glycoprotein expression was determined using Western blot analysis. The activity of P-glycoprotein was evaluated by measuring the efflux of rhodamine-123 (Rho123) in rats using an in situ single perfusion method. The changes of permeability via the paracellular route were evaluated by measuring the amount of fluorescein isothicyanate-dextran 4400 (FD-4) in a similar way. On Day 1 after LPS administration, both the level of P-glycoprotein expression and the total amount of Rho123 excreted into the intestinal lumen decreased significantly, but levels of both AUC2-95 and CLtot were not significantly different as compared with the control group. On Day 3, the total P-glycoprotein, including intestinal P-glycoprotein, might have been induced by sepsis, and then the excretion of P-glycoprotein substrate drugs into the intestinal lumen increased more than that of the control group. On Day 7, all pharmacokinetic parameters returned to the control level. Thus the intestinal P-glycoprotein function recovered within 3 days of LPS administration.
Moriguchi
Jun
J
Department of Clinical Pharmacy & Clinical Pharmacokinetics, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takastuki, Osaka 569-1043, Japan.
Kato
Ryuji
R
Nakagawa
Machiko
M
Hirotani
Yoshihiko
Y
Ijiri
Yoshio
Y
Tanaka
Kazuhiko
K
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis*; D000818:Animals; D051858:Forkhead Transcription Factors / Q000493:pharmacokinetics; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D010539:Permeability; D051381:Rats; D017208:Rats, Wistar; D020112:Rhodamine 123 / Q000378:metabolism; D029867:Xenopus Proteins / Q000493:pharmacokinetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D051858:Forkhead Transcription Factors; C424567:FoxC2a protein, Xenopus; D008070:Lipopolysaccharides; D029867:Xenopus Proteins; D020112:Rhodamine 123