title: The POR rs1057868-rs2868177 GC-GT diplotype is associated with high tacrolimus concentrations in early post-renal transplant recipients.
abstract: OBJECTIVE
  Cytochrome P450 oxidoreductase (POR) is the only flavoprotein that donates electrons to all microsomal P450 enzymes (CYP), and several POR SNPs have been shown to be important contributors to altered CYP activity or CYP-mediated drug metabolism. In this study we examined the association between 6 POR SNPs and tacrolimus concentrations in Chinese renal transplant recipients.
  
  
  METHODS
  A total of 154 renal transplant recipients were enrolled. Genotyping of CYP3A5*3 and 6 POR SNPs was performed. All patients received a triple immunosuppressive regimen comprising tacrolimus, mycophenolate mofetil and prednisone. Dose-adjusted tacrolimus trough concentrations were obtained on d 7 (C0D7/D) after transplantation when steady-state concentration of tacrolimus was achieved (dosage had been unchanged for more than 3 d).
  
  
  RESULTS
  Tacrolimus C0D7/D in CYP3A5*3/*3/ POR rs1057868-rs2868177 GC-GT diplotype carriers was 1.62- and 2.72-fold higher than those in CYP3A5*3/*3/ POR rs1057868-rs2868177 GC-GT diplotype non-carriers and CYP3A5*1 carriers (220.17±48.09 vs 135.69±6.86 and 80.84±5.27 ng/mL/mg/kg, respectively, P<0.0001). Of CYP3A5*3/*3/ POR rs1057868-rs2868177GC-GT diplotype carriers, 85.71% exceeded the upper limit of the target range (8 ng/mL), which was also significantly higher compared with the latter two groups (14.29% and 0.00%, respectively, P<0.0001). The CYP3A5*3 and POR rs1057868-rs2868177 GC-GT diplotype explained 31.7% and 5.7%, respectively, of the inter-individual variability of tacrolimus C0D7/D, whereas the POR rs1057868-rs2868177 GC-GT diplotype could explain 10.9% of the inter-individual variability of tacrolimus C0D7/D in CYP3A5 non-expressers.
  
  
  CONCLUSIONS
  The CYP3A5*3 and POR rs1057868-rs2868177 GC-GT diplotype accounted for the inter-individual variation of tacrolimus C0D7/D. Genotyping of POR rs1057868-rs2868177 diplotypes would help to differentiate initial tacrolimus dose requirements and to achieve early target C0 ranges in Chinese renal transplant recipients.
authors: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, SunYat-sen University, Guangzhou 510006, China.|Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Guangzhou 510060, China.
authors: Shu
authors: S
authors: Liu
authors: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
authors: Rong-Xin
authors: RX
authors: Chen
authors: Kidney Transplant Department, Transplant Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.
authors: Jun
authors: J
authors: Li
authors: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, SunYat-sen University, Guangzhou 510006, China.|School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 510182, China.
authors: Yu
authors: Y
authors: Zhang
authors: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, SunYat-sen University, Guangzhou 510006, China.
authors: Xue-Ding
authors: XD
authors: Wang
authors: Kidney Transplant Department, Transplant Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.
authors: Qian
authors: Q
authors: Fu
authors: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, SunYat-sen University, Guangzhou 510006, China.
authors: Ling-Yan
authors: LY
authors: Chen
authors: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, SunYat-sen University, Guangzhou 510006, China.
authors: Xiao-Man
authors: XM
authors: Liu
authors: Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Guangzhou 510060, China.
authors: Hong-Bing
authors: HB
authors: Huang
authors: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, SunYat-sen University, Guangzhou 510006, China.
authors: Min
authors: M
authors: Huang
authors: Kidney Transplant Department, Transplant Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.
authors: Chang-Xi
authors: CX
authors: Wang
authors: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, SunYat-sen University, Guangzhou 510006, China.
authors: Jia-Li
authors: JL
authors: Li
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002681:China; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004171:Diploidy; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood* / Q000627:therapeutic use; D016030:Kidney Transplantation; D008297:Male; D008499:Medical Records; D008875:Middle Aged; D000071185:Pharmacogenomic Testing; D020641:Polymorphism, Single Nucleotide; D012044:Regression Analysis; D016559:Tacrolimus / Q000008:administration & dosage / Q000097:blood* / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus