title: A Lack of Significant Effect of POR*28 Allelic Variant on Tacrolimus Exposure in Kidney Transplant Recipients.
abstract: BACKGROUND
  POR*28 is a recently newly described allelic variant of the cytochrome P450 oxidoreductase (POR), which might be associated with an increased metabolic activity of P450 cytochromes (CYP) 3A5 and 3A4. Consequently, carriers of at least 1 allele of this polymorphism could require increased calcineurin inhibitors doses to reach the target residual concentrations (C0). The objective of this study was to test whether the allelic variant of POR, which is associated with an increased metabolic activity of CYP3A, impacts tacrolimus (Tac) pharmacokinetics.
  
  
  METHODS
  We tested this hypothesis in a population of 229 kidney transplant recipients (KTR) from a large, multicenter, prospective and randomized study. We have analyzed the association between POR*28 genotype and the proportion of individuals reaching the target Tac residual concentration (Tac C0) 10 days after transplantation. We have also measured the association between POR*28 and the Tac C0, and adjusted Tac C0 (Tac C0/Tac dose) over time using generalized mixed linear models.
  
  
  RESULTS
  Ten days after transplantation, there was no difference of frequencies of KTR within the target range of Tac C0 (C0 10-15 ng/mL) according to the POR*28 genotype (P = 0.8). The mean Tac C0 at day 10 in the POR*1/*1 group was 15.3 ± 9.7 ng/mL compared with 15.7 ± 7.8 ng/mL in the POR*1/*28 group and 14.2 ± 6.8 ng/mL, in the POR*28/*28 group, P = 0.8. The adjusted Tac C0 was not associated with POR*28 genotype over time (random effects model, P = 0.9). When restricted to KTR expressing CYP3A5, POR*28 genotype did not impact the proportion of individuals within the Tac C0 target range neither the adjusted Tac C0 (random effects model, P = 0.1).
  
  
  CONCLUSIONS
  POR*28 does not significantly influence Tac pharmacokinetic parameters in a large cohort of KTR. This study does not confirm recent findings indicating that POR*28 carriers require more Tac to reach target C0.
authors.affiliation: *Department of Medical Informatics and Public Health, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris; †Paris Descartes University; Sorbonne Paris Cité, INSERM UMRS 1147; ‡Clinical Chemistry, Hôpital Européen Georges Pompidou Assistance Publique Hôpitaux de Paris; §Department of Nephrology, CHU Rouen; ¶Department of Nephrology, CHU Tours; ‖Department of Nephrology, CHU Caen; **Department of Nephrology, CHU Amiens; ††Department of Nephrology, CHU Reims; ‡‡Department of Nephrology, CHU Poitiers; §§Department of Nephrology, CHU Rennes; ¶¶Department of Nephrology, CHU Strasbourg; ‖‖Department of Nephrology, CHU Limoges; ***Department of Nephrology, CHU Clermont-Ferrand; †††Department of Nephrology, CHU Angers; ‡‡‡Department of Nephrology, Necker Hospital, Assistance Publique Hôpitaux de Paris; and §§§Department of Nephrology, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, France.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Jannot
authors.forename: Xavier
authors.initials: X
authors.lastname: Vuillemin
authors.forename: Isabelle
authors.initials: I
authors.lastname: Etienne
authors.forename: Mathias
authors.initials: M
authors.lastname: Buchler
authors.forename: Bruno
authors.initials: B
authors.lastname: Hurault de Ligny
authors.forename: Gabriel
authors.initials: G
authors.lastname: Choukroun
authors.forename: Charlotte
authors.initials: C
authors.lastname: Colosio
authors.forename: Antoine
authors.initials: A
authors.lastname: Thierry
authors.forename: Cécile
authors.initials: C
authors.lastname: Vigneau
authors.forename: Bruno
authors.initials: B
authors.lastname: Moulin
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Rerolle
authors.forename: Anne-Elizabeth
authors.initials: AE
authors.lastname: Heng
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Subra
authors.forename: Christophe
authors.initials: C
authors.lastname: Legendre
authors.forename: Philippe
authors.initials: P
authors.lastname: Beaune
authors.forename: Marie Anne
authors.initials: MA
authors.lastname: Loriot
authors.forename: Eric
authors.initials: E
authors.lastname: Thervet
authors.forename: Nicolas
authors.initials: N
authors.lastname: Pallet
mesh_terms: D000328:Adult; D000483:Alleles; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006084:Graft Rejection / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D016030:Kidney Transplantation / Q000379:methods; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D016559:Tacrolimus / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D066027:Transplant Recipients
chemical_list: D007166:Immunosuppressive Agents; C000602470:POR protein, human; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus