CYP3A5*3 and ABCB1 61A>G Significantly Influence Dose‐adjusted Trough Blood Tacrolimus Concentrations in the First Three Months Post‐Kidney Transplantation

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 (C /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 /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 /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 ) and ABCB1 61G allele carriers (p = 0.001) had lower log-transformed TAC C /D (56% and 26% lower geometric mean TAC C /D, respectively) and accounted for approximately 30% and 4%, respectively, of log-transformed TAC C /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 /D in kidney transplant recipients.

Influence of ABCB1 gene polymorphism on concentration to dose ratio and adverse effects of tacrolimus in Pakistani liver transplant recipients

“…4 Genetic polymorphism in cytochrome P4503A4, cytochrome P4503A5 and ABCB1 genes has been found to be associated with variable clinical response of tacrolimus in transplant recipients. 5,6 An important product of the ATP-binding cassette transporter (ABCB1) gene is P-glycoprotein (P-gp) which is an efflux transporter and regulates oral absorption of many drugs and endogenous substances; ABCB1 polymorphism could therefore result in altered P-gp expression and variable clinical response to tacrolimus. 6 The synonymous rs1045642A single-nucleotide polymorphism (SNP) of the ABCB1 gene in exon 26, 3435C>T may affect folding of the P-glycoprotein thereby changing the specificity of the substrate and has therefore been implicated for inter-individual variability in clinical response of tacrolimus.…”

“…5,6 An important product of the ATP-binding cassette transporter (ABCB1) gene is P-glycoprotein (P-gp) which is an efflux transporter and regulates oral absorption of many drugs and endogenous substances; ABCB1 polymorphism could therefore result in altered P-gp expression and variable clinical response to tacrolimus. 6 The synonymous rs1045642A single-nucleotide polymorphism (SNP) of the ABCB1 gene in exon 26, 3435C>T may affect folding of the P-glycoprotein thereby changing the specificity of the substrate and has therefore been implicated for inter-individual variability in clinical response of tacrolimus. 7 Transplant recipients homozygous for this variation would consequently have decreased expression of intestinal P-gp and this SNP has been reported widely in 40-45% Caucasians and less frequently in other ethnicities.…”

“… 4 Genetic polymorphism in cytochrome P4503A4, cytochrome P4503A5 and ABCB1 genes has been found to be associated with variable clinical response of tacrolimus in transplant recipients. 5 , 6 …”

Tacrolimus dose, blood concentrations and acute nephrotoxicity, but not CYP3A5/ABCB1 genetics, are associated with allograft tacrolimus concentrations in renal transplant recipients

“…The large variability in tacrolimus pharmacokinetics has been ascribed primarily to low and variable bioavailability (and clearance) due to interindividual differences in the activities of hepatic and intestinal cytochrome P450 (CYP) 3A4 and , and the efflux transporter, P‐glycoprotein (P‐gp) (reviewed in 1,6 ). A single nucleotide polymorphism (SNP) of CYP3A5 which codes for nonfunctional protein ( CYP3A5*3 , rs776746) strongly affects tacrolimus pharmacokinetics, 7–10 as does the co‐administration of P‐gp and/or CYP3A inducers or inhibitors 11,12 . However, the effects of ABCB1 SNPs on the pharmacokinetics of tacrolimus have been contradictory, 8,9,13–18 probably due to the substantial effects of CYP3A5 genetic polymorphisms and drug‐drug interactions masking a small contribution of ABCB1 polymorphisms 9,13,14,18 .…”

A Machine Learning-Based Identification of Genes Affecting the Pharmacokinetics of Tacrolimus Using the DMETTM Plus Platform

“…Therefore, identifying factors including genetic variants that affect the pharmacokinetic variability of tacrolimus may be beneficial for its optimal use. Several single nucleotide polymorphisms (SNPs) have been previously associated with tacrolimus metabolism [2][3][4][5][6][7]. For example, rs776746, also known as 6986A>G, encodes the nonfunctional CYP3A5*3 allele of the CYP3A5 gene.…”