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https://hdl.handle.net/2440/115008
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dc.contributor.author | Hu, R. | - |
dc.contributor.author | Barratt, D. | - |
dc.contributor.author | Coller, J. | - |
dc.contributor.author | Sallustio, B. | - |
dc.contributor.author | Somogyi, A. | - |
dc.date.issued | 2018 | - |
dc.identifier.citation | Basic and Clinical Pharmacology and Toxicology, 2018; 123(3):320-326 | - |
dc.identifier.issn | 1742-7835 | - |
dc.identifier.issn | 1742-7843 | - |
dc.identifier.uri | http://hdl.handle.net/2440/115008 | - |
dc.description.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. | - |
dc.description.statementofresponsibility | Rong Hu, Daniel T. Barratt, Janet K. Coller, Benedetta C. Sallustio and Andrew A. Somogyi | - |
dc.language.iso | en | - |
dc.publisher | Wiley | - |
dc.rights | © 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society) | - |
dc.source.uri | http://dx.doi.org/10.1111/bcpt.13016 | - |
dc.subject | Humans | - |
dc.subject | Tacrolimus | - |
dc.subject | Immunosuppressive Agents | - |
dc.subject | Kidney Transplantation | - |
dc.subject | Retrospective Studies | - |
dc.subject | Dose-Response Relationship, Drug | - |
dc.subject | Genotype | - |
dc.subject | Haplotypes | - |
dc.subject | Polymorphism, Single Nucleotide | - |
dc.subject | Alleles | - |
dc.subject | Adolescent | - |
dc.subject | Adult | - |
dc.subject | Aged | - |
dc.subject | Middle Aged | - |
dc.subject | Female | - |
dc.subject | Male | - |
dc.subject | Cytochrome P-450 CYP3A | - |
dc.subject | Young Adult | - |
dc.subject | Real-Time Polymerase Chain Reaction | - |
dc.subject | ATP Binding Cassette Transporter, Subfamily B | - |
dc.title | CYP3A5*3 and ABCB1 61A>G significantly influence dose-adjusted trough blood tacrolimus concentrations in the first three months post-kidney transplantation | - |
dc.type | Journal article | - |
dc.identifier.doi | 10.1111/bcpt.13016 | - |
dc.relation.grant | http://purl.org/au-research/grants/nhmrc/565038 | - |
pubs.publication-status | Published | - |
dc.identifier.orcid | Hu, R. [0000-0003-4488-1535] | - |
dc.identifier.orcid | Barratt, D. [0000-0001-6261-353X] | - |
dc.identifier.orcid | Coller, J. [0000-0002-8273-5048] | - |
dc.identifier.orcid | Sallustio, B. [0000-0002-0186-3073] | - |
dc.identifier.orcid | Somogyi, A. [0000-0003-4779-0380] | - |
Appears in Collections: | Aurora harvest 3 Pharmacology publications |
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