title: Influence of ABCB1, CYP3A4*18B and CYP3A5*3 polymorphisms on cyclosporine A pharmacokinetics in bone marrow transplant recipients.
abstract: The aim of this study was to retrospectively evaluate the effect of polymorphisms in the CYP3A4, CYP3A5 and ABCB1 genes on the dose-adjusted concentration and dose requirement of cyclosporine A(CsA) in Chinese recipients during the early period after bone marrow or hematopoietic stem cell transplantation. Ninety-one bone marrow transplant recipients were genotyped by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay or by direct sequencing for the C1236T, G2677T/A and C3435T polymorphisms in CYP3A4*18B, CYP3A5*3, and ABCB1, respectively. The concentration at zero before administration (C₀) and concentration at 2 h after administration (C₂) of whole blood CsA were measured by fluorescence polarization immunoassay. Dose-adjusted C₀ and C₂ were determined and compared among groups with different genotypes. Compared with CYP3A5*3/*3 individuals, CYP3A5*1/*1 subjects have a significantly lower dose-adjusted C₀ and C₂ at days 1-10 and a higher dose requirement for CsA at days 16-30 (p < 0.05). In addition, homozygotes for the ABCB1 3435T mutant have a significantly higher dose-adjusted C₀ and C₂ and a lower dose requirement compared with wildtype (p < 0.05). Similar results were also derived for carriers of the T-G-C haplotype in CYP3A5 producers compared with non-carriers (p < 0.05 and p < 0.01, respectively). In summary, the ABCB1 3435T SNP, T-G-C haplotype in CYP3A5 producers, and CYP3A5*3 SNP are all associated with differences in CsA pharmacokinetics and dose requirements during the first month after bone marrow or hematopoietic stem cell transplantation. Genetic testing can therefore help to determine initial dosage and individualize immunosuppressive therapy.
authors.affiliation: Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang 110004, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Qiu
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: He
authors.forename: Ya-Xin
authors.initials: YX
authors.lastname: Sun
authors.forename: Jesse
authors.initials: J
authors.lastname: Li-Ling
authors.forename: Li-Mei
authors.initials: LM
authors.lastname: Zhao
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D016026:Bone Marrow Transplantation / Q000379:methods; D002648:Child; D002675:Child, Preschool; D002681:China; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D016231:Fluorescence Polarization Immunoassay; D005838:Genotype; D006239:Haplotypes; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D008297:Male; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D055815:Young Adult
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; C510163:CYP3A4 protein, human