title: Influence of CYP3A5 and ABCB1 gene polymorphisms and other factors on             tacrolimus dosing in Caucasian liver and kidney transplant patients.
abstract: Tacrolimus is a substrate of cytochrome P4503A (CYP3A) enzymes as well as of the drug transporter ABCB1. We have investigated the possible influence of CYP3A5 and ABCB1 single nucleotide polymorphisms (SNPs) and other factors (e.g. albumin, hematocrit and steroids) on tacrolimus blood levels achieved in a population of Caucasian liver (n=51) and kidney (n=50) transplant recipients. At 1, 3 and 6 months after transplantation, tacrolimus doses (mg/kg/day) and trough blood levels (C0) were recorded and the weight-adjusted tacrolimus dosage (mg/kg/day) was calculated. Polymerase chain reaction followed by restriction fragment length polymorphism analysis was used for genotyping CYP3A5*1 and *3 [6986A>G] as well as ABCB1 at exons 21 [2677G>T/A] and 26 [3435C>T] in both liver transplant donors and recipients and in kidney transplant recipients. Of the 152 subjects studied, 84.9% showed a CYP3A5*3/*3 genotype. The total frequency of the allelic variant *3 was 93%. For the G2677T/A and C3435T polymorphisms the total frequencies of the allelic variants T/A and T were 44.7 and 46.7%, respectively. At 1, 3 and 6 months after transplantation the dose-adjusted C0 levels were significantly lower in patients with one copy of the *1 allele compared to those homozygous for the *3 allele. In the case of liver transplant patients the tacrolimus dose requirements were dominantly influenced by the polymorphisms of the CYP3A5 gene in the donors. With regard to the ABCB1 SNPs, in general they did not show any appreciable influence on tacrolimus dosing requirements; however, kidney transplant recipients carrying the 2677T/A allele required significantly higher daily tacrolimus doses than subjects homozygous for the wild-type allele. Identification of CYP3A5 single nucleotide polymorphisms prior to transplantation could contribute to evaluate the appropriate initial dosage of tacrolimus in the patients.
authors.affiliation: Department of Clinical Pharmacy, ISMETT, Via E. Tricomi 1, I-90127 Palermo, Italy. katrin.lochner@med.uni-rostock.de
authors.forename: Alessio
authors.initials: A
authors.lastname: Provenzani
authors.forename: Monica
authors.initials: M
authors.lastname: Notarbartolo
authors.forename: Manuela
authors.initials: M
authors.lastname: Labbozzetta
authors.forename: Paola
authors.initials: P
authors.lastname: Poma
authors.forename: Giovanni
authors.initials: G
authors.lastname: Vizzini
authors.forename: Paola
authors.initials: P
authors.lastname: Salis
authors.forename: Chiara
authors.initials: C
authors.lastname: Caccamo
authors.forename: Tullio
authors.initials: T
authors.lastname: Bertani
authors.forename: Ugo
authors.initials: U
authors.lastname: Palazzo
authors.forename: Piera
authors.initials: P
authors.lastname: Polidori
authors.forename: Bruno
authors.initials: B
authors.lastname: Gridelli
authors.forename: Natale
authors.initials: N
authors.lastname: D'Alessandro
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D000368:Aged; D000483:Alleles; D054316:Biomarkers, Pharmacological; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004252:DNA Mutational Analysis; D054796:Drug Dosage Calculations; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000378:metabolism; D007558:Italy; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016030:Kidney Transplantation; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D016559:Tacrolimus / Q000008:administration & dosage* / Q000378:metabolism; D044465:White People / Q000235:genetics*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D054316:Biomarkers, Pharmacological; D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus