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Contribution of down-regulation of intestinal and hepatic cytochrome P450 3A to increased absorption of cyclosporine A in a rat nephrosis model.

Abstract
This study examined the contribution of changes in regulation of intestinal and hepatic cytochrome P450 3A (CYP3A) and multidrug resistance transporter 1 (Mdr1) to absorption of cyclosporine A (CsA) in a rat nephrosis model. Interleukin (IL)-6 was also measured. Puromycin aminonucleoside at a dose of 20 mg/100 g was administered intravenously. Tissue samples were dissected out from the upper and middle intestines and liver after development of nephrosis to measure the expression levels of mRNA and protein. CsA at a dose of 0.5 mg/100 g was administered into a closed loop of the upper and middle intestines. Blood from the inferior vena cava (IVC) and portal vein was taken until 30 min after administration. The expression levels of CYP3A decreased markedly, whereas those of Mdr1 showed large interindividual variations for all of the tissues in the nephrotic rats. Plasma concentrations of CsA reached higher levels in the nephrotic than in the control rats and were higher when administered from the upper than the middle intestine in both the portal vein and IVC. IL-6 increased in urine in the nephrotic rats. In summary, intestinal and hepatic CYP3A were down-regulated in the nephrosis model accompanying the increased levels of IL-6. Consistent results were not obtained for the regulation of Mdr1. In conclusion, these findings suggest that the down-regulation of CYP3A in the upper intestine and liver predominantly contributes to the increase in CsA absorption, and Mdr1 showed less contribution in this rat nephrosis model.
AuthorsTomoe Fujita, Shuichi Yasuda, Yuji Kamata, Kazumi Fujita, Yoshio Ohtani, Yuji Kumagai, Masataka Majima
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 327 Issue 2 Pg. 592-9 (Nov 2008) ISSN: 1521-0103 [Electronic] United States
PMID18725544 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Cytochrome P-450 CYP3A Inhibitors
  • Interleukin-6
  • RNA, Messenger
  • Puromycin Aminonucleoside
  • Cyclosporine
  • Cytochrome P-450 CYP3A
Topics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 (analysis, genetics)
  • Animals
  • Cyclosporine (pharmacokinetics)
  • Cytochrome P-450 CYP3A (genetics, physiology)
  • Cytochrome P-450 CYP3A Inhibitors
  • Disease Models, Animal
  • Down-Regulation
  • Interleukin-6 (urine)
  • Intestines (enzymology)
  • Liver (enzymology)
  • Male
  • Nephrosis (chemically induced, metabolism)
  • Puromycin Aminonucleoside (toxicity)
  • RNA, Messenger (analysis)
  • Rats
  • Rats, Sprague-Dawley

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