title: Influence of CYP3A5 genetic polymorphism on tacrolimus daily dose requirements and acute rejection in renal graft recipients.
abstract: Tacrolimus is a widely used immunosuppressive drug in organ transplantation. Its oral bioavailability varies greatly between individuals, and it is a substrate of cytochrome P450 3A (CYP3A) and P-glycoprotein. Our objective was to determine the influence of CYP3A5 and ABCB1 genetic polymorphisms on tacrolimus daily requirements and on transplantation outcome. One hundred and thirty-six renal graft recipients treated with tacrolimus were genotyped for CYP3A5 (6986A>G), ABCB1 exon26 (3435C>T) and exon21 (2677G>T/A) single nucleotide polymorphisms. Genotypes were correlated to tacrolimus daily dose at 1-week, 1-, 6- and 12-month post-transplantation and with transplantation outcome. At 1-month post-transplantation, tacrolimus daily dose was higher for patients with CYP3A5*1/*1 genotype compared to CYP3A5*3/*3 genotype (0.26 +/- 0.03 versus 0.16 +/- 0.01 mg/kg/day, respectively, P < 0.0001). Similar results were obtained at 6- and 12-month post-transplantation. Furthermore, CYP3A5*1 homozygotes were associated with increased risk of acute rejection episodes compared to patients with CYP3A5*1/*3 and CYP3A5*3/*3 genotypes (38% versus 10% and 9%, respectively, P = 0.01). CYP3A5 genetic polymorphism was not associated with tacrolimus-related nephrotoxicity. ABCB1 polymorphisms were not related with transplantation outcome. CYP3A5 genetic polymorphism appeared in our study to affect tacrolimus daily dose requirements and transplantation outcome. Screening for this single nucleotide polymorphism before the transplantation might be helpful for the selection of adequate initial daily dose and to achieve the desired immunosuppression.
authors.affiliation: Pharmacology Department, Pierre et Marie Curie University, Saint Antoine University Hospital, Paris, France. lina.quteineh@yahoo.com
authors.forename: Lina
authors.initials: L
authors.lastname: Quteineh
authors.forename: Céline
authors.initials: C
authors.lastname: Verstuyft
authors.forename: Valerie
authors.initials: V
authors.lastname: Furlan
authors.forename: Antoine
authors.initials: A
authors.lastname: Durrbach
authors.forename: Alexia
authors.initials: A
authors.lastname: Letierce
authors.forename: Sophie
authors.initials: S
authors.lastname: Ferlicot
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Taburet
authors.forename: Bernard
authors.initials: B
authors.lastname: Charpentier
authors.forename: Laurent
authors.initials: L
authors.lastname: Becquemont
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000208:Acute Disease; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006084:Graft Rejection / Q000201:enzymology / Q000517:prevention & control*; D006785:Hospitals, University; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D010045:Outpatients; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D012307:Risk Factors; D016559:Tacrolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
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; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus