Vanhove Thomas, de Jonge Hylke, de Loor Henriëtte, Annaert Pieter, Diczfalusy Ulf, Kuypers Dirk R J
Department of Microbiology and Immunology, KU Leuven - University of Leuven, Leuven, Belgium.
Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.
Br J Clin Pharmacol. 2016 Dec;82(6):1539-1549. doi: 10.1111/bcp.13083. Epub 2016 Sep 20.
We compared the CYP3A4 metrics weight-corrected midazolam apparent oral clearance (MDZ Cl/F/W) and plasma 4β-hydroxycholesterol/cholesterol (4β-OHC/C) as they relate to tacrolimus (TAC) Cl/F/W in renal transplant recipients.
For a cohort of 147 patients, 8 h area under the curve (AUC) values for TAC and oral MDZ were calculated besides measurement of 4β-OHC/C. A subgroup of 70 patients additionally underwent intravenous erythromycin breath test (EBT) and were administered the intravenous MDZ probe. All patients were genotyped for common polymorphisms in CYP3A4, CYP3A5 and P450 oxidoreductase, among others.
MDZ Cl/F/W, 4β-OHC/C/W, EBT and TAC Cl/F/W were all moderately correlated (r = 0.262-0.505). Neither MDZ Cl/F/W nor 4β-OHC/C/W explained variability in TAC Cl/F/W in CYP3A5 expressors (n = 29). For CYP3A5 non-expressors (n = 118), factors explaining variability in TAC Cl/F/W in a MDZ-based model were MDZ Cl/F/W (R = 0.201), haematocrit (R = 0.139), TAC formulation (R = 0.107) and age (R = 0.032; total R = 0.479). In the 4β-OHC/C/W-based model, predictors were 4β-OHC/C/W (R = 0.196), haematocrit (R = 0.059) and age (R = 0.057; total R = 0.312). When genotype information was ignored, predictors of TAC Cl/F/W in the whole cohort were 4β-OHC/C/W (R = 0.167), MDZ Cl/F/W (R = 0.045); Tac QD formulation (R = 0.036), and haematocrit (R = 0.032; total R = 0.315). 4β-OHC/C/W, but not MDZ Cl/F/W, was higher in CYP3A5 expressors because it was higher in CYP3A4*1b carriers, which were almost all CYP3A5 expressors.
A MDZ-based model explained more variability in TAC clearance in CYP3A5 non-expressors. However, 4β-OHC/C/W was superior in a model in which no genotype information was available, likely because 4β-OHC/C/W was influenced by the CYP3A4*1b polymorphism.
我们比较了肾移植受者中与他克莫司（TAC）清除率校正体重后的口服咪达唑仑表观清除率（MDZ Cl/F/W）和血浆4β-羟基胆固醇/胆固醇（4β-OHC/C）之间的关系。
对147例患者的队列，除了测量4β-OHC/C外，还计算了TAC和口服MDZ的8小时曲线下面积（AUC）值。70例患者的亚组另外接受了静脉注射红霉素呼气试验（EBT）并给予静脉注射MDZ探针。所有患者均对CYP3A4、CYP3A5和P450氧化还原酶等常见多态性进行基因分型。
MDZ Cl/F/W、4β-OHC/C/W、EBT和TAC Cl/F/W均呈中度相关（r = 0.262 - 0.505）。在CYP3A5表达者（n = 29）中，MDZ Cl/F/W和4β-OHC/C/W均不能解释TAC Cl/F/W的变异性。对于CYP3A5非表达者（n = 118），基于MDZ的模型中解释TAC Cl/F/W变异性的因素有MDZ Cl/F/W（R = 0.201）、血细胞比容（R = 0.139）、TAC剂型（R = 0.107）和年龄（R = 0.032；总R = 0.479）。在基于4β-OHC/C/W的模型中，预测因素为4β-OHC/C/W（R = 0.196）、血细胞比容（R = 0.059）和年龄（R = 0.057；总R = 0.312）。当忽略基因型信息时，整个队列中TAC Cl/F/W的预测因素为4β-OHC/C/W（R = 0.167）、MDZ Cl/F/W（R = 0.045）；他克莫司一日一次剂型（R = 0.036）和血细胞比容（R = 0.032；总R = 0.315）。4β-OHC/C/W在CYP3A5表达者中较高，而MDZ Cl/F/W则不然，因为它在CYP3A4*1b携带者中较高，而这些携带者几乎都是CYP3A5表达者。
基于MDZ的模型在解释CYP3A5非表达者中TAC清除率的变异性方面表现更好。然而，在没有基因型信息的模型中，4β-OHC/C/W更具优势，可能是因为4β-OHC/C/W受CYP3A4*1b多态性的影响。
