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Open AccessArticle

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

1
Department of Clinical Pharmacology and Biopharmaceutics, The Pharmaceutical College, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
2
Department of Pharmacy, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
3
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
4
Department of Pharmacy, International University of Health and Welfare Narita Hospital, 852 Hatakeda, Narita 286-0124, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(7), 2287; https://doi.org/10.3390/ijms21072287 (registering DOI)
Received: 4 March 2020 / Revised: 22 March 2020 / Accepted: 24 March 2020 / Published: 26 March 2020
(This article belongs to the Special Issue Molecular Mechanisms and Biomarkers in Drug-Induced Organ Injury)
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. View Full-Text
Keywords: tacrolimus; CYP3A5*3; POR*28; liver transplantation; biomarker tacrolimus; CYP3A5*3; POR*28; liver transplantation; biomarker
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Nakamura, T.; Fukuda, M.; Matsukane, R.; Suetsugu, K.; Harada, N.; Yoshizumi, T.; Egashira, N.; Mori, M.; Masuda, S. Influence of POR*28 Polymorphisms on CYP3A5*3-Associated Variations in Tacrolimus Blood Levels at an Early Stage after Liver Transplantation. Int. J. Mol. Sci. 2020, 21, 2287.

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