Abstract
CYP3A5 gene polymorphism in recipients plays an important role in tacrolimus blood pharmacokinetics after renal transplantation. Even though CYP3A5 protein is expressed in renal tubular cells, little is known about the influence on the tacrolimus intrarenal exposure and hence graft outcome. The aim of our study was to investigate how the tacrolimus intrarenal concentration (Ctissue) could be predicted based on donor CYP3A5 gene polymorphism in renal transplant recipients. A total of 52 Japanese renal transplant patients receiving tacrolimus were enrolled in this study. Seventy-four renal biopsy specimens were obtained at 3 months and 1 year after transplantation to determine the donor CYP3A5 polymorphism and measure the Ctissue by liquid chromatography-tandem mass spectrometry (LC-MS-MS). The tacrolimus Ctissue ranged from 52 to 399 pg/mg tissue (n = 74) and was weak but significantly correlated with tacrolimus trough concentration (C0) at 3 months after transplantation (Spearman, r = 0.3560, p = 0.0096). No significant relationship was observed between the donor CYP3A5 gene polymorphism and Ctissue or Ctissue/C0. These data showed that the tacrolimus systemic level has an impact on tacrolimus renal accumulation after renal transplantation. However, donor CYP3A5 gene polymorphism alone cannot be used to predict tacrolimus intrarenal exposure. This study may be valuable for exploring tacrolimus renal metabolism and toxicology mechanism in renal transplant recipients.
Highlights
Tacrolimus is a commonly used calcineurin inhibitor (CNI) for immunosuppressive therapy to prevent allograft rejection after renal transplantation
We focused on evaluating the capability of utilizing donor CYP3A5 gene polymorphism to predict tacrolimus Ctissue in renal transplant recipients
We evaluated the influence of the donor and recipient CYP3A5 polymorphism on tacrolimus pharmacokinetics by assessing C0 and dose-adjusted C0 (C0/D) of tacrolimus
Summary
Tacrolimus is a commonly used calcineurin inhibitor (CNI) for immunosuppressive therapy to prevent allograft rejection after renal transplantation. With a narrow therapeutic index and high inter-patient pharmacokinetic variability, monitoring the tacrolimus trough concentration (C0) in whole blood has been recommended in post-transplantation clinical routine to optimize the therapy outcome and minimize adverse effects [1,2]. Some studies have hypothesized that tacrolimus intrarenal concentration (Ctissue) could be affected by the graft CYP3A5 gene polymorphism (donor genotype) and suggested that the tacrolimus intrarenal levels could be a better predictor of histological AR than blood concentrations [10,15]. There have been only two studies that have preliminarily measured the tacrolimus concentration in human kidney tissues [16,17], and little clinical information is available about association between the donor CYP3A5 gene polymorphism and tacrolimus renal metabolism. We focused on evaluating the capability of utilizing donor CYP3A5 gene polymorphism to predict tacrolimus Ctissue in renal transplant recipients
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