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Type: Journal article
Title: CYP3A5*3 and ABCB1 61A>G significantly influence dose-adjusted trough blood tacrolimus concentrations in the first three months post-kidney transplantation
Author: Hu, R.
Barratt, D.
Coller, J.
Sallustio, B.
Somogyi, A.
Citation: Basic and Clinical Pharmacology and Toxicology, 2018; 123(3):320-326
Publisher: Wiley
Issue Date: 2018
ISSN: 1742-7835
Statement of
Rong Hu, Daniel T. Barratt, Janet K. Coller, Benedetta C. Sallustio and Andrew A. Somogyi
Abstract: Tacrolimus (TAC) is a first-line immunosuppressant used to prevent organ rejection after kidney transplantation. There is large inter-individual variability in its pharmacokinetics. Single nucleotide polymorphisms (SNPs) in genes encoding TAC metabolizing enzymes cytochromes P450 3A4/5 (CYP3A4/5), P-glycoprotein efflux transporter (ABCB1), their expression regulator pregnane X receptor (NR1I2) and CYP3A co-factor cytochrome P450 reductase (POR) have been studied for their effects on tacrolimus disposition. However, except for CYP3A5*3, controversies remain about their roles in predicting dose-adjusted trough blood TAC concentrations (C0 /D). This study aimed to investigate the effects of ABCB1 (61A>G, 1199G>A, 1236C>T, 2677G>T and 3435C>T), CYP3A4*22, CYP3A5*3, NR1I2 (8055C>T, 63396C>T and -25385C>T) and POR*28 SNPs on TAC C₀/D. In total, 165 kidney transplant recipients were included in this study. SNPs were genotyped by probe-based real-time polymerase chain reaction. Associations between log-transformed whole blood TAC C₀/D (measured at 1 and 3 months post-transplant) and genotypes/haplotypes were assessed by linear mixed effects analysis, controlling for age, sex and haematocrit. It was observed that CYP3A5 expressors (*1/*1 + *1/*3) (p = 5.5 × 10⁻¹⁶ ) and ABCB1 61G allele carriers (p = 0.001) had lower log-transformed TAC C₀/D (56% and 26% lower geometric mean TAC C₀/D, respectively) and accounted for approximately 30% and 4%, respectively, of log-transformed TAC C₀/D variability in the first 3 months post-transplant. In conclusion, CYP3A5*3 is a major, and ABCB1 61A>G is a novel, although minor, genetic factor affecting TAC C₀/D in kidney transplant recipients.
Keywords: Humans
Immunosuppressive Agents
Kidney Transplantation
Retrospective Studies
Dose-Response Relationship, Drug
Polymorphism, Single Nucleotide
Middle Aged
Cytochrome P-450 CYP3A
Young Adult
Real-Time Polymerase Chain Reaction
ATP Binding Cassette Transporter, Subfamily B
Rights: © 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
DOI: 10.1111/bcpt.13016
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