Pharmaceutical and genetic determinants for interindividual differences of tacrolimus bioavailability in renal transplant recipients
Pharmaceutical and genetic determinants for interindividual differences of tacrolimus bioavailability in renal transplant recipients
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DOI：
10.1007/s00228-013-1514-8
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发表时间：
2013-09-01
影响因子：
2.9
通讯作者：
Satoh, Shigeru
中科院分区：
文献类型：
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作者：
Niioka, Takenori;Kagaya, Hideaki;Satoh, Shigeru
他克莫司口服速释每日两次（BID）和缓释每日一次（QD）制剂的药代动力学具有较高的个体间变异性。我们调查了影响肾移植患者他克莫司生物利用度个体间变异性的因素。97例日本肾移植患者（47例他克莫司BID组和50例他克莫司QD组）入选本研究。采用0 - 24 h药时曲线下面积计算他克莫司的绝对生物利用度在同一受体中连续静脉输注和口服他克莫司制剂后的AUC（0-24）。（四分位数1-四分位数3）他克莫司QD组中，CYP 3A 5 *1或CYP 3A 5 *3/*3等位基因受体的他克莫司相对生物利用度显著较低[9.1%（6.3- 10.7%）和15.4%（11.5- 18.7%）]比他克莫司BID组[分别为12.6%（9.9- 14.2%）和19.3%（16.5- 24.8%）]（分别为P = 0.004和0.028）。因此，他克莫司绝对生物利用度最低的接受者与CYP 3A 5 *1等位基因服用他克莫司QD。CYP 3A 5基因多态性对持续静脉输注他克莫司的剂量校正AUC（0-24）无影响（P = 0.906），口服制剂他克莫司生物利用度的个体间差异较大似乎是由于CYP 3A 5基因多态性和他克莫司口服制剂的影响。因此，在确定他克莫司个体化给药时应考虑这些因素。
The pharmacokinetics of orally administered immediate-release, twice-daily (BID) and modified-release, once-daily (QD) formulations of tacrolimus have high interindividual variability. We investigated factors affecting interindividual variability of tacrolimus bioavailability in renal transplant patients.Ninety-seven Japanese renal transplant patients (47 patients on tacrolimus BID and 50 patients on tacrolimus QD) were enrolled in this study. The tacrolimus absolute bioavailability was calculated using the area under the concentration-time curve from 0 to 24 h (AUC(0-24)) after continuous intravenous infusion and oral formulations of tacrolimus in the same recipient.The median (quartile 1-quartile 3) tacrolimus relative bioavailability for recipients with the CYP3A5*1 or CYP3A5*3/*3 alleles was significantly lower for the tacrolimus QD group [9.1 % (6.3-10.7 %) and 15.4 % (11.5-18.7 %), respectively] than for the tacrolimus BID group [12.6 % (9.9-14.2 %) and 19.3 % (16.5-24.8 %), respectively] (P = 0.004 and 0.028, respectively). Consequently, tacrolimus absolute bioavailability was lowest for recipients with the CYP3A5*1 allele taking tacrolimus QD. The CYP3A5 polymorphism had no impact on the dose-adjusted AUC(0-24) of tacrolimus in patients on continuous intravenous infusion (P = 0.906).The larger interindividual variability of tacrolimus bioavailability for oral formulations appears to be due to the effects of the CYP3A5 polymorphism and the tacrolimus oral formulation. These factors should therefore be taken into account when determining individualized tacrolimus dosing.