title: Pharmacogenetic aspects of the use of tacrolimus in renal transplantation: recent developments and ethnic considerations.
abstract: BACKGROUND
  Tacrolimus (Tac) is effective in preventing acute rejection but has considerable toxicity and inter-individual variability in pharmacokinetics and pharmacodynamics. Part of this is explained by polymorphisms in genes encoding Tac-metabolizing enzymes and transporters. A better understanding of Tac pharmacokinetics and pharmacodynamics may help to minimize different outcomes amongst transplant recipients by personalizing immunosuppression.
  
  
  METHODS
  The pharmacogenetic contribution of Tac metabolism will be examined, with a focus on recent discoveries, new developments and ethnic considerations.
  
  
  CONCLUSIONS
  The strongest and most consistent association in pharmacogenetics is between the CYP3A5 genotype and Tac dose requirement, with CYP3A5 expressers having a ~ 40-50% higher dose requirement compared to non-expressers. Two recent randomized-controlled clinical trials using CYP3A5 genotype, however, did not show a decrease in acute rejections nor reduced toxicity. CYP3A4*22, CYP3A4*26, and POR*28 are also associated with Tac dose requirements and may be included to provide the expected improvement of Tac therapy. Studies focusing on the intracellular drug concentrations and on calcineurin inhibitor-induced nephrotoxicity also seem promising. For all studies, however, the ethnic prevalence of genotypes should be taken into account, as this may significantly impact the effect of pre-emptive genotyping.
authors.affiliation: a Department of Laboratory Medicine , West China Hospital of Sichuan University , Chengdu , China.|b Department of Hospital Pharmacy , Erasmus MC, University Medical Center Rotterdam , Rotterdam , The Netherlands.
authors.forename: J T
authors.initials: JT
authors.lastname: Tang
authors.affiliation: b Department of Hospital Pharmacy , Erasmus MC, University Medical Center Rotterdam , Rotterdam , The Netherlands.
authors.forename: L M
authors.initials: LM
authors.lastname: Andrews
authors.affiliation: b Department of Hospital Pharmacy , Erasmus MC, University Medical Center Rotterdam , Rotterdam , The Netherlands.|c Department of Internal Medicine, Division of Nephrology and Renal Transplantation , Erasmus MC, University Medical Center Rotterdam , Rotterdam , The Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: van Gelder
authors.affiliation: d Department of Nephrology , West China Hospital of Sichuan University , Chengdu , China.
authors.forename: Y Y
authors.initials: YY
authors.lastname: Shi
authors.affiliation: e Department of Clinical Chemistry , Erasmus MC, University Medical Center Rotterdam , Rotterdam , The Netherlands.
authors.forename: R H N
authors.initials: RH
authors.lastname: van Schaik
authors.affiliation: a Department of Laboratory Medicine , West China Hospital of Sichuan University , Chengdu , China.
authors.forename: L L
authors.initials: LL
authors.lastname: Wang
authors.affiliation: c Department of Internal Medicine, Division of Nephrology and Renal Transplantation , Erasmus MC, University Medical Center Rotterdam , Rotterdam , The Netherlands.
authors.forename: D A
authors.initials: DA
authors.lastname: Hesselink
mesh_terms: D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005006:Ethnicity; D005838:Genotype; D006084:Graft Rejection / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016030:Kidney Transplantation / Q000379:methods*; D010597:Pharmacogenetics / Q000379:methods; D011110:Polymorphism, Genetic; D057285:Precision Medicine / Q000379:methods; D016032:Randomized Controlled Trials as Topic; D016559:Tacrolimus / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D007166:Immunosuppressive Agents; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus
keywords: Calcineurin inhibitor; cytochrome P450; ethnicity; kidney; pharmacodynamics; pharmacogenetics; pharmacokinetics; tacrolimus; transplanation