Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/115008
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dc.contributor.authorHu, R.-
dc.contributor.authorBarratt, D.-
dc.contributor.authorColler, J.-
dc.contributor.authorSallustio, B.-
dc.contributor.authorSomogyi, A.-
dc.date.issued2018-
dc.identifier.citationBasic and Clinical Pharmacology and Toxicology, 2018; 123(3):320-326-
dc.identifier.issn1742-7835-
dc.identifier.issn1742-7843-
dc.identifier.urihttp://hdl.handle.net/2440/115008-
dc.description.abstractTacrolimus (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.-
dc.description.statementofresponsibilityRong Hu, Daniel T. Barratt, Janet K. Coller, Benedetta C. Sallustio and Andrew A. Somogyi-
dc.language.isoen-
dc.publisherWiley-
dc.rights© 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)-
dc.source.urihttp://dx.doi.org/10.1111/bcpt.13016-
dc.subjectHumans-
dc.subjectTacrolimus-
dc.subjectImmunosuppressive Agents-
dc.subjectKidney Transplantation-
dc.subjectRetrospective Studies-
dc.subjectDose-Response Relationship, Drug-
dc.subjectGenotype-
dc.subjectHaplotypes-
dc.subjectPolymorphism, Single Nucleotide-
dc.subjectAlleles-
dc.subjectAdolescent-
dc.subjectAdult-
dc.subjectAged-
dc.subjectMiddle Aged-
dc.subjectFemale-
dc.subjectMale-
dc.subjectCytochrome P-450 CYP3A-
dc.subjectYoung Adult-
dc.subjectReal-Time Polymerase Chain Reaction-
dc.subjectATP Binding Cassette Transporter, Subfamily B-
dc.titleCYP3A5*3 and ABCB1 61A>G significantly influence dose-adjusted trough blood tacrolimus concentrations in the first three months post-kidney transplantation-
dc.typeJournal article-
dc.identifier.doi10.1111/bcpt.13016-
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/565038-
pubs.publication-statusPublished-
dc.identifier.orcidHu, R. [0000-0003-4488-1535]-
dc.identifier.orcidBarratt, D. [0000-0001-6261-353X]-
dc.identifier.orcidColler, J. [0000-0002-8273-5048]-
dc.identifier.orcidSallustio, B. [0000-0002-0186-3073]-
dc.identifier.orcidSomogyi, A. [0000-0003-4779-0380]-
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