Site-dependent contributions of P-glycoprotein and CYP3A to cyclosporin A absorption, and effect of dexamethasone in small intestine of mice.
We examined whether the oral bioavailability of cyclosporin A is controlled primarily by P-glycoprotein (P-gp) or CYP3A in the small intestine. In situ loop method was used to evaluate the uptake of cyclosporin A (40nmol) at the upper and lower intestine of wild-type and mdr1a/1b knockout mice treated or not treated with dexamethasone (75mg/kg/day, 7 days, i.p.). Expression of CYP3A mRNA in the control group was higher in the upper than the lower intestine, while that of the multidrug resistance-1a (mdr1a) mRNA was in the opposite order. Dexamethasone administration potently induced CYP3A and mdr1a mRNAs in the lower and upper intestine, respectively. At 45min after cyclosporin A administration into an upper intestinal loop of the control group of wild-type mice, the ratio of residual cyclosporin A to dose did not differ significantly from that of mdr1a/1b knockout mice, whereas in dexamethasone-treated wild-type mice, the residual ratio was increased significantly. The ratio of the cyclosporin A metabolite M17 to cyclosporin A in portal venous blood at an upper intestinal loop of mdr1a/1b knockout mice was much higher than that a lower intestinal loop. The M17/cyclosporin A ratio of portal venous blood at a lower intestinal loop in mdr1a/1b knockout mice was increased significantly by dexamethasone treatment. These results suggest that, under physiological conditions, the oral bioavailability of cyclosporin A is mainly controlled by CYP3A in the upper intestine, rather than liver, but when P-gp is induced by steroid, the intestinal absorption of cyclosporin A may be inhibited.
Jin
Mingji
M
Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa 920-1192, Japan.
Shimada
Tsutomu
T
Yokogawa
Koichi
K
Nomura
Masaaki
M
Ishizaki
Junko
J
Piao
Yingshi
Y
Kato
Yukio
Y
Tsuji
Akira
A
Miyamoto
Ken-Ichi
K
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001682:Biological Availability; D016572:Cyclosporine / Q000097:blood / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D007408:Intestinal Absorption; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008861:Microsomes / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D000097202:ATP-Binding Cassette Sub-Family B Member 4; D008565:Membrane Proteins
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D016572:Cyclosporine; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D003907:Dexamethasone; D012333:RNA, Messenger; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C095122:multidrug resistance protein 3; C496508:Cyp3a11 protein, mouse; D008565:Membrane Proteins