title: Pharmacogenetic study of ABCB1 and CYP3A5 genes during the first year following heart transplantation regarding tacrolimus or cyclosporine levels.
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 (C(0)/(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.
authors.affiliation: Servicio de Farmacia, Hospital Universitario La Fe, Valencia, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Jordán de Luna
authors.forename: M J
authors.initials: MJ
authors.lastname: Herrero Cervera
authors.forename: I
authors.initials: I
authors.lastname: Sánchez Lázaro
authors.forename: L
authors.initials: L
authors.lastname: Almenar Bonet
authors.forename: J L
authors.initials: JL
authors.lastname: Poveda Andrés
authors.forename: S F
authors.initials: SF
authors.lastname: Aliño Pellicer
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D016572:Cyclosporine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D054796:Drug Dosage Calculations; D016903:Drug Monitoring; D005787:Gene Frequency; D005838:Genotype; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics*; D015810:Linkage Disequilibrium; D010597:Pharmacogenetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D013030:Spain; D016559:Tacrolimus / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; D016572:Cyclosporine; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus