Pharmacogenetic Study of ABCB1 and CYP3A5 Genes During the First Year Following Heart Transplantation Regarding Tacrolimus or Cyclosporine Levels

• Published in: Transplantation proceedings Vol. 43; no. 6; pp. 2241 - 2243
• Main Authors: Jordán de Luna, C, Herrero Cervera, M.J, Sánchez Lázaro, I, Almenar Bonet, L, Poveda Andrés, J.L, Aliño Pellicer, S.F
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Amsterdam Elsevier Inc 01-07-2011; Elsevier
• Subjects: Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; ATP Binding Cassette Transporter, Sub-Family B; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Biological and medical sciences; Cyclosporine - administration & dosage; Cyclosporine - blood; Cyclosporine - pharmacokinetics; Cytochrome P-450 CYP3A - genetics; Cytochrome P-450 CYP3A - metabolism; Drug Dosage Calculations; Drug Monitoring; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene Frequency; Genotype; Heart Transplantation; Humans; Immunosuppressive Agents - blood; Immunosuppressive Agents - pharmacokinetics; Linkage Disequilibrium; Medical sciences; Pharmacogenetics; Pharmacology. Drug treatments; Phenotype; Polymorphism, Single Nucleotide; Spain; Surgery; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Surgery of the heart; Tacrolimus - administration & dosage; Tacrolimus - blood; Tacrolimus - pharmacokinetics; Tissue, organ and graft immunology; Heart; Pharmacogenetics; Calcineurin inhibitor; Enzyme; Cytochrome P450; Lactone; Homotransplantation; Macrolide; Immunomodulator; Medicine; Treatment; Tacrolimus; Surgery; MDR-1 gene; Genetics; Graft; Ciclosporin; Cardiac transplantation; Circulatory system; Protein synthesis inhibitor; Immunosuppressive agent; Antibacterial agent
• ISSN: 0041-1345; 1873-2623
• DOI: 10.1016/j.transproceed.2011.05.008

Abstract Pharmacogenetics explains part of the interindividual variability in drug responses. Many published works about the effects of single nucleotide polymorphisms (SNPs) on immunosuppressive drug blood levels present contradictory results. We evaluated the SNPs in ABCB1 (glycoprotein P) and CYP3A5 (metabolic enzyme) genes, seeking correlate them with tacrolimus or cyclosporine levels during the first year after heart transplantation. One blood sample was obtained from each of 41 patients: 26 treated with cyclosporine and 15 with tacrolimus. We characterize the SNPs rs1045642, 1128503, 2032582, 2235013, 2235033, 2229109, 3213619, 9282564 in ABCB1 and rs10264272, 776746 in CYP3A5 genes using the Sequenom platform. The genotype was correlated with the trough drug blood levels corrected by dose and body weight (C0 /(dose/weight)). The CYP3A5 SNPs showed the expected behavior, where patients carrying the low expression variants displayed higher drug blood levels of more than 100% of the normal expression variant level even at 1 year posttransplantation. To correlate ABCB1 SNPs, the variants described to cause higher blood levels in rs1045642, 1128503, 2032582 (in linkage disequilibrium) showed this effect only until 4 months posttransplantation among patients treated with cyclosporine (more than 100% higher than the other variant). After 1 year, concentrations reached a stable phase with normal levels. The observation was not so evident among those treated with tacrolimus. Remarkably, at this point, patients treated with cyclosporine, showed a significant ( P < .01) difference between the two variants of rs9282564 and even if it was not significant there was also a tendency among the intronic rs2235013 and 2235033. The results indicated that SNPs in ABCB1 gene seem to not be relevant for long-term dose adjustment in patients, but to show an effect during the first 4 months.