title: Personalized tacrolimus doses determined by CYP3A5 genotype for induction and maintenance phases of kidney transplantation.
abstract: BACKGROUND
  Cytochrome P450 (CYP) 3A4 and 3A5 are major isoforms involved in the metabolism of tacrolimus, with the CYP3A5 gene being more polymorphic. It is hypothesized that individual variation in the metabolism of tacrolimus drug may result from genetic polymorphism of CYP3A5. It has been reported that the clearance of tacrolimus in patients with the CYP3A5*1 allele was ~2.5-fold greater than that in those with the CYP3A5*3/*3 genotype. Recent data have also shown that polymorphism in exon 26 (C3435T) of the multidrug resistance gene (MDR1) was correlated with the expression level and function of P-glycoprotein in the lower duodenum, making the relationship between polymorphism of MDR1 and the effective dose of tacrolimus a source of controversy.
  
  
  OBJECTIVE
  This study investigated the influence of genetic polymorphisms of CYP3A5 and MDR1 on the dose requirements for the induction and maintenance phases of tacrolimus therapy in kidney transplant recipients.
  
  
  METHODS
  Sixty-eight kidney transplant recipients were enrolled, and their clinical and laboratory data were retrospectively reviewed after 6 months of tacrolimus administration. Genotypes of CYP3A5*1 and CYP3A5*3 and exon 26 of MDR1 (C3435T) were determined by the single-nucleotide polymorphism genotyping method.
  
  
  RESULTS
  The frequencies of CYP3A5*3/*3, CYP3A5*1/*3, and CYP3A5*1/*1 were 44.1%, 35.3%, and 20.6%, respectively. The mean dose of tacrolimus required for the induction phase was significantly greater in the CYP3A5*1/*1 group (0.142 [0.050] mg/kg/d) than that required in the CYP3A5*1/*3 group (0.097 [0.040] mg/kg/d; P = 0.072) and in the CYP3A5*3/*3 group (0.077 [0.020] mg/kg/d; P = 0.005). The maintenance dose of tacrolimus required in the CYP3A5*1/*1 group (0.12 [0.03] mg/kg/d) was 1.3-fold higher than that in the CYP3A5*1/*3 group (0.09 [0.03] mg/kg/d; P = 0.018) and 2.4-fold higher than in the CYP3A5*3/*3 group (0.05 [0.02] mg/kg/d; P < 0.0001). No statistically significant relationship was observed between the doses of tacrolimus required for the induction and maintenance phases and MDR1 polymorphism.
  
  
  CONCLUSIONS
  Determination of the CYP3A5 genotype would be helpful in the design of adequate immunosuppressive treatment and in lowering toxicity by predicting the doses of tacrolimus required for the induction and maintenance phases in individual kidney transplant recipients.
authors.affiliation: Pharmacology. Electronic address: sudvan@kku.ac.th.
authors.forename: Suda
authors.initials: S
authors.lastname: Vannaprasaht
authors.forename: Sirirat
authors.initials: S
authors.lastname: Reungjui
authors.forename: Darika
authors.initials: D
authors.lastname: Supanya
authors.forename: Dhavee
authors.initials: D
authors.lastname: Sirivongs
authors.forename: Cholatip
authors.initials: C
authors.lastname: Pongskul
authors.forename: Yingyos
authors.initials: Y
authors.lastname: Avihingsanon
authors.forename: Wichittra
authors.initials: W
authors.lastname: Tassaneeyakul
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000328:Adult; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005091:Exons; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D016559:Tacrolimus / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use
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; C510163:CYP3A4 protein, human; D016559:Tacrolimus
keywords: CYP3A5 genotype; dosage regimen; induction dose; kidney transplantation; maintenance dose; tacrolimus