Initial dosage adjustment for oral administration of tacrolimus using the intestinal MDR1 level in living-donor liver transplant recipients

The role of intestinal P-glycoprotein (encoded by the MDR1/ABCB1 gene) and/or metabolic enzyme CYP3A4 for tacrolimus therapy was examined in recipients of living-donor liver transplantation (LDLT), under the hypothesis that these proteins are factors for pharmacokinetic variability. The intestinal mRNA expression level of MDR1 and CYP3A4 was evaluated by real-time polymerase chain reaction (PCR), using the upper jejunum from a part of the Roux-en-Y limb for biliary reconstruction at LDLT. For 7 days postoperatively, good inverse correlation was found between the tacrolimus concentration/dose (C/D) ratio and the intestinal mRNA level of MDR1 (r = -0.776), but not of CYP3A4 (r = -0.096), in the 46 cases. After classifying the patients according to median of the intestinal MDR1 mRNA expression, the oral dose of tacrolimus in the high-MDR1 group was approximately twofold higher than in the low-MDR1 group (P < .001), whereas its trough level was similar between the two groups. In addition, the correlation between the intestinal MDR1 mRNA level and the tacrolimus C/D ratio was confirmed with a larger population (r = -0.645, n = 104). Using the regression line between the intestinal MDR1 mRNA level and tacrolimus C/D ratio, we could prospectively predict the individual C/D ratio of tacrolimus immediately after LDLT. Known genetic variations of the MDR1 gene had no effect on intestinal MDR1 mRNA level and tacrolimus C/D ratio in LDLT patients. This suggests that the intestinal mRNA level of MDR1 is a useful molecular marker for determination of the personalized oral dose of tacrolimus in recipients of LDLT immediately after surgery.

在活体肝移植（LDLT）受者中，对肠道P -糖蛋白（由MDR1/ABCB1基因编码）和/或代谢酶CYP3A4在他克莫司治疗中的作用进行了研究，基于的假设是这些蛋白质是药代动力学变异的因素。通过实时聚合酶链反应（PCR）评估MDR1和CYP3A4的肠道mRNA表达水平，使用LDLT中用于胆道重建的部分Roux - en - Y肠袢的空肠上段。在术后7天，在46例患者中发现他克莫司浓度/剂量（C/D）比值与MDR1的肠道mRNA水平呈良好的负相关（r = -0.776），但与CYP3A4的肠道mRNA水平无相关性（r = -0.096）。根据肠道MDR1 mRNA表达的中位数对患者进行分类后，高MDR1组他克莫司的口服剂量大约是低MDR1组的两倍（P <.001），而两组的谷浓度相似。此外，在更大的人群中证实了肠道MDR1 mRNA水平与他克莫司C/D比值之间的相关性（r = -0.645，n = 104）。利用肠道MDR1 mRNA水平与他克莫司C/D比值之间的回归线，我们可以前瞻性地预测LDLT术后即刻他克莫司的个体C/D比值。已知的MDR1基因遗传变异对LDLT患者的肠道MDR1 mRNA水平和他克莫司C/D比值没有影响。这表明MDR1的肠道mRNA水平是术后即刻确定LDLT受者他克莫司个体化口服剂量的有用分子标志物。