Jannot Anne-Sophie, Vuillemin Xavier, Etienne Isabelle, Buchler Mathias, Hurault de Ligny Bruno, Choukroun Gabriel, Colosio Charlotte, Thierry Antoine, Vigneau Cécile, Moulin Bruno, Rerolle Jean-Philippe, Heng Anne-Elizabeth, Subra Jean-Francois, Legendre Christophe, Beaune Philippe, Loriot Marie Anne, Thervet Eric, Pallet Nicolas
*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.
Ther Drug Monit. 2016 Apr;38(2):223-9. doi: 10.1097/FTD.0000000000000267.
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.
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 POR28 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 POR28 and the Tac C0, and adjusted Tac C0 (Tac C0/Tac dose) over time using generalized mixed linear models.
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 POR28 genotype (P = 0.8). The mean Tac C0 at day 10 in the POR1/1 group was 15.3 ± 9.7 ng/mL compared with 15.7 ± 7.8 ng/mL in the POR1/28 group and 14.2 ± 6.8 ng/mL, in the POR28/28 group, P = 0.8. The adjusted Tac C0 was not associated with POR28 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).
POR28 does not significantly influence Tac pharmacokinetic parameters in a large cohort of KTR. This study does not confirm recent findings indicating that POR28 carriers require more Tac to reach target C0.
POR*28是细胞色素P450氧化还原酶（POR）最近新描述的一种等位基因变体，可能与细胞色素P450（CYP）3A5和3A4的代谢活性增加有关。因此，这种多态性至少携带1个等位基因的个体可能需要增加钙调神经磷酸酶抑制剂的剂量才能达到目标残余浓度（C0）。本研究的目的是测试与CYP3A代谢活性增加相关的POR等位基因变体是否会影响他克莫司（Tac）的药代动力学。
我们在一项大型、多中心、前瞻性随机研究的229名肾移植受者（KTR）群体中检验了这一假设。我们分析了POR28基因型与移植后10天达到目标他克莫司残余浓度（Tac C0）的个体比例之间的关联。我们还测量了POR28与Tac C0之间的关联，并使用广义混合线性模型随时间调整Tac C0（Tac C0/Tac剂量）。
移植后10天，根据POR28基因型，Tac C0目标范围（C0 10 - 15 ng/mL）内的KTR频率没有差异（P = 0.8）。POR1/1组第10天的平均Tac C0为15.3±9.7 ng/mL，POR1/28组为15.7±7.8 ng/mL，POR28/28组为14.2±6.8 ng/mL，P = 0.8。随时间调整的Tac C0与POR28基因型无关（随机效应模型，P = 0.9）。当仅限于表达CYP3A5的KTR时，POR*28基因型既不影响Tac C0目标范围内个体的比例，也不影响调整后的Tac C0（随机效应模型，P = 0.1）。
在一大群KTR中，POR28对Tac药代动力学参数没有显著影响。本研究未证实最近的研究结果，即POR28携带者需要更多的Tac才能达到目标C0。
