Kuypers Dirk R, de Jonge Hylke, Naesens Maarten, Vanrenterghem Yves
Department of Nephrology and Renal Transplantation, University Hospitals Leuven, University of Leuven, Leuven, Belgium.
Pharmacogenet Genomics. 2008 Oct;18(10):861-8. doi: 10.1097/FPC.0b013e328307c26e.
Drug interactions between tacrolimus and azole antifungals are characterized by a large clinical variability. The aim of this study was to examine the influence of the CYP3A4, CYP3A5, and MDR1 single nucleotide polymorphisms on changes in tacrolimus exposure and dosing in renal allograft recipients treated with fluconazole.
Twenty-nine patients who had received documented fluconazole treatment were identified out of a total of 753 renal recipients on maintenance tacrolimus therapy. These 29 patients were genotyped for CYP3A4*1/1B, CYP3A51/*3, MDR1 C3435T, and G2677T/A, and the influence of the latter polymorphisms on tacrolimus exposure and dose before, during, and after fluconazole administration was examined.
Dose-corrected trough blood tacrolimus concentration did not change significantly from baseline (1.26+/-1.23-fold) in heterozygous CYP3A51 carriers during exposure to fluconazole, in contrast to homozygous CYP3A53 carriers (3.28+/-2.34-fold; P=0.04 between CYP3A53/3 and CYP3A53/1 genotypes). Homozygous CYP3A53 carriers experienced a significant decrease of weight-corrected tacrolimus dose requirements during fluconazole administration (54.7+/-23.7% from baseline, P<0.05) in contrast to heterozygous carriers of CYP3A51 (25.1+/-29.9%; P=0.07 between CYP3A5*3/3 and CYP3A53/1 genotypes). These findings were not influenced by fluconazole dose or duration of administration. Significantly more CYP3A53/3 carriers were exposed to tacrolimus dose-uncorrected trough blood tacrolimus concentration value greater than or equal to 15 ng/ml during administration of fluconazole compared with CYP3A53/*1 carriers (73.9 vs. 16.7%, P=0.01).
In renal allograft recipients the CYP3A5*3/*1 genotype is associated with a reduced susceptibility for the inhibitory effects of fluconazole on tacrolimus metabolism, thereby identifying a genetic determinant of the clinical variability of CYP3A-mediated drug interactions.
他克莫司与唑类抗真菌药之间的药物相互作用具有较大的临床变异性。本研究旨在探讨CYP3A4、CYP3A5和MDR1单核苷酸多态性对接受氟康唑治疗的肾移植受者他克莫司暴露量及剂量变化的影响。
在753例接受他克莫司维持治疗的肾移植受者中，确定了29例接受过氟康唑治疗的患者。对这29例患者进行CYP3A4*1/1B、CYP3A51/*3、MDR1 C3435T和G2677T/A基因分型，并研究后几种多态性对氟康唑给药前、给药期间和给药后他克莫司暴露量及剂量的影响。
在接触氟康唑期间，杂合子CYP3A51携带者的剂量校正后他克莫司谷血浓度与基线相比无显著变化（1.26±1.23倍），而纯合子CYP3A53携带者则有显著变化（3.28±2.34倍；CYP3A53/3和CYP3A53/1基因型之间P=0.04）。与CYP3A5×1杂合子携带者相比，纯合子CYP3A53携带者在氟康唑给药期间体重校正后的他克莫司剂量需求显著降低（较基线降低54.7±23.7%，P<0.05）（CYP3A5*3/3和CYP3A53/1基因型之间P=0.07）。这些发现不受氟康唑剂量或给药持续时间的影响。与CYP3A53/1携带者相比，在氟康唑给药期间，显著更多的CYP3A53/*3携带者暴露于未校正剂量的他克莫司谷血浓度值大于或等于15 ng/ml的情况（73.9%对16.7%，P=0.01）。
在肾移植受者中，CYP3A5*3/*1基因型与氟康唑对他克莫司代谢抑制作用的敏感性降低有关，从而确定了CYP3A介导的药物相互作用临床变异性的一个遗传决定因素。
