title: Do drug transporter (ABCB1) SNPs and P-glycoprotein function influence cyclosporine and macrolides exposure in renal transplant patients? Results of the pharmacogenomic substudy within the symphony study.
abstract: The function of the efflux pump P-glycoprotein (Pgp) and ABCB1 single nucleotide polymorphisms (SNPs) should be considered as important tools to deepen knowledge of drug nephrotoxicity and disposition mechanisms. The aim of this study is to investigate the association of C3435T, G2677T, C1236T, and T129C ABCB1 SNPs with Pgp activity and exposure to different immunosuppressive drugs in renal transplant patients. Patients included in the Symphony Pharmacogenomic substudy were genotyped for ABCB1 SNPs. According to the design, patients were randomized into four immunosuppressive regimens: low and standard dose of cyclosporine (n = 30), tacrolimus (n = 13), and sirolimus (n = 23) concomitantly with mycophenolate and steroids. Pgp activity was evaluated in PBMC using the Rhodamine 123 efflux assay. TT carrier patients on C3435T, G2677T, and C1236T SNPs (Pgp-low pumpers) showed lower Pgp activity than noncarriers. Pgp-high pumpers treated with cyclosporine showed lower values of Pgp function than macrolides. There was a negative correlation between cyclosporine AUC and Pgp activity at 3 months. Results did not show any correlation between tacrolimus and sirolimus AUC and Pgp activity at 3 months. We found an important role of the ABCB1 SNPs Pgp function in CD3(+)  peripheral blood lymphocytes from renal transplant recipients. Pgp activity was influenced by cyclosporine but not macrolides exposure.
authors.affiliation: Nephrology Service and Laboratory of Experimental Nephrology, Hospital Universitari de Bellvitge, Barcelona, Spain.
authors.forename: Inés
authors.initials: I
authors.lastname: Llaudó
authors.forename: Helena
authors.initials: H
authors.lastname: Colom
authors.forename: Pepita
authors.initials: P
authors.lastname: Giménez-Bonafé
authors.forename: Joan
authors.initials: J
authors.lastname: Torras
authors.forename: Anna
authors.initials: A
authors.lastname: Caldés
authors.forename: Maria
authors.initials: M
authors.lastname: Sarrias
authors.forename: Josep M
authors.initials: JM
authors.lastname: Cruzado
authors.forename: Federico
authors.initials: F
authors.lastname: Oppenheimer
authors.forename: Jaime
authors.initials: J
authors.lastname: Sánchez-Plumed
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: Gentil
authors.forename: Henrik
authors.initials: H
authors.lastname: Ekberg
authors.forename: Josep M
authors.initials: JM
authors.lastname: Grinyó
authors.forename: Núria
authors.initials: N
authors.lastname: Lloberas
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D017252:CD3 Complex / Q000378:metabolism; D016572:Cyclosporine / Q000627:therapeutic use*; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000502:physiology*; D007963:Leukocytes, Mononuclear / Q000166:cytology; D018942:Macrolides / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D013256:Steroids / Q000627:therapeutic use
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017252:CD3 Complex; D007166:Immunosuppressive Agents; D018942:Macrolides; D013256:Steroids; D016572:Cyclosporine