title: Cytochrome P450 genetic polymorphisms influence the serum concentration of calcineurin inhibitors in allogeneic hematopoietic SCT recipients.
abstract: Calcineurin inhibitors are necessary as immunosuppressants during hematopoietic SCT (HSCT) to prevent alloreactivity, but have unfortunate toxicities. So, we investigated the association of gene polymorphisms with the initial calcineurin inhibitor concentration and the subsequent drug dose from day 1 to day 28 among patients who underwent HSCT at a single institution. We analyzed 58 serial cases of Japanese patients receiving GVHD prophylaxis with CsA (21 cases) or tacrolimus (37 cases). We investigated eight single-nucleotide polymorphisms: rs4244285 (CYP2C19), rs15524, rs4646450, rs3800959, rs776746 (CYP3A5), rs1128503, rs2032582 and rs1045642 (MDR1). The CsA concentration was significantly higher when the genotype of CYP3A5 rs15524 was T/T (P=0.044) or rs776746 was G/G (P=0.027). The CYP3A5 rs776746 and rs4646450 genotypes were also associated with tacrolimus concentration (P=0.013 and P=0.0058, respectively). The dosage of tacrolimus was remarkably reduced from day -1 to day 28 when the patient had the CYP3A5 rs4646450 C/C and/or rs776746 G/G genotype (P=0.0010 and P=0.0021, respectively). In this study, we show that genetic variation has a predictable effect on the pharmacological responses to calcineurin inhibitors in HSCT patients.
authors.affiliation: Department of Hematology and Oncology, Tokai University School of Medicine, Kanagawa, Japan. moni@xf6.so-net.ne.jp
authors.forename: M
authors.initials: M
authors.lastname: Onizuka
authors.forename: N
authors.initials: N
authors.lastname: Kunii
authors.forename: M
authors.initials: M
authors.lastname: Toyosaki
authors.forename: S
authors.initials: S
authors.lastname: Machida
authors.forename: D
authors.initials: D
authors.lastname: Ohgiya
authors.forename: Y
authors.initials: Y
authors.lastname: Ogawa
authors.forename: H
authors.initials: H
authors.lastname: Kawada
authors.forename: H
authors.initials: H
authors.lastname: Inoko
authors.forename: K
authors.initials: K
authors.lastname: Ando
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000328:Adult; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D005838:Genotype; D006086:Graft vs Host Disease / Q000517:prevention & control; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016559:Tacrolimus / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D016559:Tacrolimus