Premium
CYP3A5*3 and ABCB1 61A>G Significantly Influence Dose‐adjusted Trough Blood Tacrolimus Concentrations in the First Three Months Post‐Kidney Transplantation
Author(s) -
Hu Rong,
Barratt Daniel T.,
Coller Janet K.,
Sallustio Benedetta C.,
Somogyi Andrew A.
Publication year - 2018
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.13016
Subject(s) - tacrolimus , single nucleotide polymorphism , cyp3a4 , pharmacology , cyp3a5 , cyp3a , pregnane x receptor , medicine , kidney transplantation , pharmacokinetics , whole blood , transplantation , kidney , genotype , endocrinology , chemistry , cytochrome p450 , gene , biochemistry , metabolism , transcription factor , nuclear receptor
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 (C 0 /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 C 0 /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 C 0 /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 C 0 /D (56% and 26% lower geometric mean TAC C 0 /D, respectively) and accounted for approximately 30% and 4%, respectively, of log‐transformed TAC C 0 /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 C 0 /D in kidney transplant recipients.