QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.108.142091v1 327/2/592    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Fujita, T. Articles by Majima, M. Search for Related Content PubMed PubMed Citation Articles by Fujita, T. Articles by Majima, M.

METABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Contribution of Down-Regulation of Intestinal and Hepatic Cytochrome P450 3A to Increased Absorption of Cyclosporine A in a Rat Nephrosis Model

Departments of Pharmacology (T.F., Y.Ku., M.M.) and Nephrology (K.F.) and Center for Genetic Studies of Integrated Biological Functions (S.Y.), Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan; Department of Endocrinology, Diabetes and Metabolism, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, Japan (Y.Ka.); Syounan Sakura Clinic, Chigasaki, Kanagawa, Japan (Y.O.); and Clinical Investigation Center, Kitasato University East Hospital, Sagamihara, Kanagawa, Japan (T.F., Y.Ku.)

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.

Address correspondence to: Dr. Tomoe Fujita, Department of Pharmacology, Kitasato University School of Medicine, Kitasato 1-15-1, Sagamihara, Kanagawa 228-8555, Japan. E-mail address: fujita-t{at}kitasato-u.ac.jp