Fujita Tomoe, Yasuda Shuichi, Kamata Yuji, Fujita Kazumi, Ohtani Yoshio, Kumagai Yuji, Majima Masataka
Department of Pharmacology, Kitasato University School of Medicine, Kitasato 1-15-1, Sagamihara, Kanagawa 228-8555, Japan.
J Pharmacol Exp Ther. 2008 Nov;327(2):592-9. doi: 10.1124/jpet.108.142091. Epub 2008 Aug 25.
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.
本研究在大鼠肾病模型中，考察了肠道和肝脏细胞色素P450 3A（CYP3A）及多药耐药转运蛋白1（Mdr1）调控变化对环孢素A（CsA）吸收的影响。同时检测了白细胞介素（IL）-6水平。静脉注射剂量为20 mg/100 g的嘌呤霉素核苷。肾病形成后，从大鼠的上、中肠及肝脏切取组织样本，检测mRNA和蛋白质表达水平。将剂量为0.5 mg/100 g的CsA注入上、中肠的闭合肠袢。给药后30分钟内，采集下腔静脉（IVC）和门静脉血样。肾病大鼠所有组织中，CYP3A的表达水平显著降低，而Mdr1的表达水平个体差异较大。肾病大鼠血浆中CsA浓度高于对照大鼠，且经门静脉和IVC给药时，上肠给药后的CsA浓度高于中肠给药。肾病大鼠尿中IL-6水平升高。总之，在IL-6水平升高的肾病模型中，肠道和肝脏CYP3A表达下调。未得到Mdr1调控的一致结果。综上所述，这些发现表明，上肠和肝脏中CYP3A的下调主要导致了CsA吸收增加，而在该大鼠肾病模型中，Mdr1的作用较小。
