Elevated blood concentrations of calcineurin inhibitors during diarrheal episode in pediatric liver transplant recipients: Involvement of the suppression of intestinal cytochrome P450 3A and P-glycoprotein
Elevated blood concentrations of calcineurin inhibitors during diarrheal episode in pediatric liver transplant recipients: Involvement of the suppression of intestinal cytochrome P450 3A and P-glycoprotein
复制标题
DOI：
10.1111/j.1399-3046.2005.00315.x
复制
发表时间：
2005-06-01
影响因子：
1.3
通讯作者：
Fujimura, A
中科院分区：
文献类型：
--
作者：
Maezono, S;Sugimoto, K;Fujimura, A
我们遇到了两例儿童活体肝移植受者，他们在腹泻发作期间血液中环孢素或他克莫司(细胞色素P450 （CYP) 3A和p -糖蛋白（P-gp）的双重底物）浓度升高。为了研究肠道炎症对代谢和外排泵活性的影响，我们采用脂多糖（LPS）诱导的肠道损伤模型进行了实验。采用硝苯地平氧化法测定大鼠肠上皮微粒体的CYP3A活性。采用地高辛通量与大鼠切除肠灌流系统结合，检测P-gp的药物外排。腹腔注射LPS （0.3 mg/kg）可显著降低肠上皮细胞CYP3A活性41% （p < 0.01）。在大鼠空肠近段，与对照组相比，地高辛的黏膜至浆膜通量显著增加（p < 0.05）。经肠上皮吸收的地高辛向黏膜灌注液的外排在LPS处理的空肠中明显减弱（p < 0.05），说明LPS处理降低了大鼠小肠p -gp活性。这些发现提示，抑制CYP3A和P-gp活性可能参与了肠炎腹泻期间环孢素和他克莫司血药浓度升高的机制。为防止药物引起的不良反应，在此类发作期间应减少作为CYP3A或P-gp底物的药物的剂量。
We encountered two cases of pediatric living-related liver transplant recipients who showed increases in blood concentration of cyclosporine or tacrolimus, a dual substrate for cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp), during a diarrheal episode. To investigate the effect of intestinal inflammation on the metabolic and efflux pump activities, we conducted the experiments using the lipopolysaccharide (LPS)-induced intestinal damage model. Intestinal epithelial CYP3A activity was assessed by nifedipine oxidation using intestinal epithelial microsomes in rat. Drug efflux by P-gp was tested using digoxin flux with the excised intestine perfusion system in rats. Intraperitoneal injection of LPS (0.3 mg/kg) significantly reduced the intestinal epithelial CYP3A activity by 41% (p < 0.01). In the proximal jejunal segment of the rats treated with LPS, mucosal to serosal flux of digoxin was significantly enhanced compared to that of control (p < 0.05). Efflux of digoxin, which was taken up by intestinal epithelium, to mucosal perfusate was significantly blunted in the jejunum treated with LPS (p < 0.05), which indicates that the LPS treatment reduced the P-gp activity in rat small intestine. These findings suggest that the suppression of CYP3A and P-gp activities may be involved in the mechanism of elevated blood concentrations of cyclosporine and tacrolimus during enteritis-induced diarrhea. To prevent a drug-induced adverse effect, dose of a drug, which is a substrate of CYP3A or P-gp, should be reduced during such an episode.