Contribution of down-regulation of intestinal and hepatic cytochrome P450 3A to increased absorption of cyclosporine A in a rat nephrosis model.
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.
Fujita
Tomoe
T
Department of Pharmacology, Kitasato University School of Medicine, Kitasato 1-15-1, Sagamihara, Kanagawa 228-8555, Japan. fujita-t@kitasato-u.ac.jp
Yasuda
Shuichi
S
Kamata
Yuji
Y
Fujita
Kazumi
K
Ohtani
Yoshio
Y
Kumagai
Yuji
Y
Majima
Masataka
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis / Q000235:genetics; D000818:Animals; D016572:Cyclosporine / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000502:physiology*; D065692:Cytochrome P-450 CYP3A Inhibitors; D004195:Disease Models, Animal; D015536:Down-Regulation; D015850:Interleukin-6 / Q000652:urine; D007422:Intestines / Q000201:enzymology*; D008099:Liver / Q000201:enzymology*; D008297:Male; D009401:Nephrosis / Q000139:chemically induced / Q000378:metabolism*; D011692:Puromycin Aminonucleoside / Q000633:toxicity; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065692:Cytochrome P-450 CYP3A Inhibitors; D015850:Interleukin-6; D012333:RNA, Messenger; D011692:Puromycin Aminonucleoside; D016572:Cyclosporine; D051544:Cytochrome P-450 CYP3A