Site-dependent contributions of P-glycoprotein and CYP3A to cyclosporin A absorption, and effect of dexamethasone in small intestine of mice

フォーマット:

論文

責任表示:

Jin, Ingji ; Shimada, Tsutomu ; Yokogawa, Koichi ; Nomura, Masaaki ; Ishizaki, Junko ; Piao, Yingshi ; Kato, Yukio ; Tsuji, Akira ; Miyamoto, Kenichi

言語:

英語

出版情報:

Elsevier BV, 2006-10-01

著者名:

Jin, Ingji

Shimada, Tsutomu

Yokogawa, Koichi

Nomura, Masaaki

Ishizaki, Junko

Piao, Yingshi

Kato, Yukio

Tsuji, Akira

Miyamoto, Kenichi

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掲載情報:

Biochemical Pharmacology

ISSN:

0006-2952      

巻:

72

通号:

8

開始ページ:

1042

終了ページ:

1050

バージョン:

author

概要:

金沢大学医学部附属病院薬剤部<br />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 ( … 40 nmol) at the upper and lower intestine of wild-type and mdr1a/1b knockout mice treated or not treated with dexamethasone (75 mg/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 45 min 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. © 2006 Elsevier Inc. All rights reserved. 続きを見る

URL:

http://hdl.handle.net/2297/2958