title: Frequencies and roles of CYP3A5, CYP3A4 and ABCB1 single nucleotide polymorphisms in Italian teenagers after kidney transplantation.
abstract: The main genes involved in the pharmacokinetics of immunosuppressive drugs are those encoding cytochrome P450 (CYP) family enzymes and multidrug resistance 1 (ABCB1). In this study, 87 Italian teenagers with transplanted kidneys (mean age 11.6 ± 4.8 years) receiving calcineurin inhibitors (CNIs) were genotyped for the single nucleotide polymorphisms (SNPs) CYP3A5*1/3 and CYP3A4*1B for CYP3A, and C1236T, G2677T/A, C3435T and IVS21+49 for ABCB1, and retrospectively evaluated for the influence of the screened SNPs on CNI blood level at different post-transplantation times. The CYP3A5*1 allele was present in 7% of the patients, and the CYP3A4*1B allele was present in 3% of patients. The ABCB1 C1236T, G2677T/A and C3435T SNPs C, G and T occurred frequently (55%, 53% and 54%, respectively). The frequency of the T allele of IVS21+49 was 86%. The frequency of SNPs in both genes was comparable with that reported in other European Caucasian populations but different from that found in Asians or Afro-Americans. None of the cyclosporine (CsA) pharmacokinetic parameters were associated with the CYP3A5 genetic polymorphism, whereas the presence of the A allele in some patients was responsible for the required administration of a significantly increased dose of tacrolimus (Tac) that was necessary to reach therapeutic target levels. None of the Tac pharmacokinetic parameters were associated with ABCB1 SNPs, but ABCB1 SNPs had early effects on the CsA exposure index and dose requirements. In conclusion, because SNPs of the CYP3A and ABCB1 genes may be associated with CNI pharmacokinetic parameters and exposure indices, pre-transplant genetic screening should be considered in order to avoid immunosuppressant-related adverse events.
authors.affiliation: Pediatric Nephrology Unit, Ospedale Maggiore IRCCS, Via F. Sforza 35, 20133 Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Turolo
authors.forename: Amedea S
authors.initials: AS
authors.lastname: Tirelli
authors.forename: Mariano
authors.initials: M
authors.lastname: Ferraresso
authors.forename: Luciana
authors.initials: L
authors.lastname: Ghio
authors.forename: Mirco
authors.initials: M
authors.lastname: Belingheri
authors.forename: Elena
authors.initials: E
authors.lastname: Groppali
authors.forename: Erminio
authors.initials: E
authors.lastname: Torresani
authors.forename: Alberto
authors.initials: A
authors.lastname: Edefonti
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000483:Alleles; D065095:Calcineurin Inhibitors; D002648:Child; D016572:Cyclosporine / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D020641:Polymorphism, Single Nucleotide; D016559:Tacrolimus / Q000009:adverse effects / 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; D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D016559:Tacrolimus