Influence of POR*28 Polymorphisms on CYP3A5*3-Associated Variations in Tacrolimus Blood Levels at an Early Stage after Liver Transplantation

摘要

It is well known that the polymorphism is an important marker that correlates with the tacrolimus dose requirement after organ transplantation. Recently, it has been revealed that the polymorphism affects the pharmacokinetics of tacrolimus in renal transplant patients. In this study, we examined whether as well as polymorphism in Japanese recipients and donors would be another biomarker for the variation of tacrolimus blood levels in the recipients during the first month after living-donor liver transplantation. We enrolled 65 patients treated with tacrolimus, who underwent liver transplantation between July 2016 and January 2019. Genomic DNA was extracted from whole-blood samples, and genotyping was performed to examine the presence of and polymorphisms in the recipients and donors. The genotype (defective CYP3A5) of the recipient (standard partial regression coefficient [median C/D ratio of expressor vs. non-expressor, value]: Pod 1–7, β= −0.389 [1.76 vs. 2.73, < 0.001]; Pod 8–14, β = −0.345 [2.03 vs. 2.83, < 0.001]; Pod 15–21, β= −0.417 [1.75 vs. 2.94, < 0.001]; Pod 22–28, β = −0.627 [1.55 vs. 2.90, < 0.001]) rather than donor (Pod 1–7, β = n/a [1.88 vs. 2.76]; Pod 8–14, β = n/a [1.99 vs. 2.93]; Pod 15–21, β = −0.175 [1.91 vs. 2.94, = 0.004]; Pod 22–28, β = n/a [1.61 vs. 2.67]) significantly contributed to the increase in the concentration/dose (C/D) ratio of tacrolimus for at least one month after surgery. We found that the tacrolimus C/D ratio significantly decreased from the third week after transplantation when the recipient carried both (functional CYP3A5) and ( = 19 [29.2%], median C/D ratio [inter quartile range] = 1.58 [1.39–2.17]), compared with that in the recipients carrying and ( = 8 [12.3%], median C/D ratio [inter quartile range] = 2.23 [2.05–3.06]) ( < 0.001). In conclusion, to our knowledge, this is the first report suggesting that the polymorphism is another biomarker for the tacrolimus oral dosage after liver transplantation in patients carrying * rather than *3/ .