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

Abstract

It is well known that the CYP3A5*3 polymorphism is an important marker that correlates with the tacrolimus dose requirement after organ transplantation. Recently, it has been revealed that the POR*28 polymorphism affects the pharmacokinetics of tacrolimus in renal transplant patients. In this study, we examined whether POR*28 as well as CYP3A5*3 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 CYP3A5*3 and POR*28 polymorphisms in the recipients and donors. The CYP3A5*3/*3 genotype (defective CYP3A5) of the recipient (standard partial regression coefficient [median C/D ratio of CYP3A5 expressor vs. CYP3A5 non-expressor, p value]: Pod 1–7, β= −0.389 [1.76 vs. 2.73, p < 0.001]; Pod 8–14, β = −0.345 [2.03 vs. 2.83, p < 0.001]; Pod 15–21, β= −0.417 [1.75 vs. 2.94, p < 0.001]; Pod 22–28, β = −0.627 [1.55 vs. 2.90, p < 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, p = 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 CYP3A5*1 (functional CYP3A5) and POR*28 (n = 19 [29.2%], median C/D ratio [inter quartile range] = 1.58 [1.39–2.17]), compared with that in the recipients carrying CYP3A5*1 and POR*1/*1 (n = 8 [12.3%], median C/D ratio [inter quartile range] = 2.23 [2.05–3.06]) (p < 0.001). In conclusion, to our knowledge, this is the first report suggesting that the POR*28 polymorphism is another biomarker for the tacrolimus oral dosage after liver transplantation in patients carrying CYP3A5*1 rather than CYP3A5*3/*3.

CYP3A5 Genotype as a Potential Pharmacodynamic Biomarker for Tacrolimus Therapy in Ulcerative Colitis in Japanese Patients

“…It is reported that the influence of CYP3A5 is greater than that of CYP3A4 on the metabolism of tacrolimus [ 18 , 19 , 20 ]. However, in the CYP3A5 genotype, the efficacy of tacrolimus is affected and, therefore, a dose adjustment based on this genotype is required after organ transplantation [ 21 , 22 , 23 ]. Therefore, in the treatment of UC, the pharmacokinetics and effects of tacrolimus may be altered in the CYP3A5 genotype [ 24 ].…”

CYP3A5 and POR gene polymorphisms as predictors of infection and graft rejection in post-liver transplant patients treated with tacrolimus - a cohort study

“…The T allele of the POR gene (rs1057868) is associated with increased CYP3A5 activity (16,17). Justifying that, patients carrying the T allele of the POR gene (expressers) have higher enzyme activity, low tacrolimus concentrations and high doses of immunosuppressants (17)(18)(19), favoring the development of infections.…”

Artificial Neural Network Analysis of Determinants of Tacrolimus Pharmacokinetics in Liver Transplant Recipients

“…For example, singlenucleotide polymorphisms in the gene CYP3A5 in liver transplant (LT) recipients and donors affect tacrolimus PK; in particular, donor genotype at CYP3A5 influences prognosis soon after liver transplantation. [4][5][6][7][8][9][10] The CYP3A5*1 encodes a functional cytochrome P450 enzyme, which can metabolize tacrolimus and reduce its bioavailability, whereas the CYP3A5*3 allele contains premature termination codons that give rise to truncated, nonfunctional enzyme. 4,11,12 For the same tacrolimus dose, individuals with a CYP3A5*3*3 genotype show a higher drug concentration in the blood than individuals with genotypes *1*1 or *1*3.…”