title: The influence of pharmacogenetics and cofactors on clinical outcomes in kidney transplantation.
abstract: BACKGROUND
  Immunosuppressive drugs have a narrow therapeutic range and large inter-individual response variability. This has prompted pharmacogenetic studies, mostly with regard to their dose-concentration relationships, but also about proteins involved in their pharmacodynamics. Some polymorphisms of genes involved in their disposition pathways were shown to affect their dose-concentration relationships. The impact of pharmacogenetics on tissue distribution and the resulting clinical effects have less often been studied. More importantly, a few single nucleotide polymorphisms seem to have a significant impact on the incidence of acute rejection or the adverse effects of immunosuppressants. Environmental factors often interact with such genotype-phenotype relationships.
  
  
  METHODS
  This article reviews the impact of genetic polymorphisms of the metabolic enzymes, membrane transporters and target proteins of mycophenolic acid, calcineurin inhibitors and mammalian target of rapamycin inhibitors on clinical outcomes in kidney transplantation.
  
  
  CONCLUSIONS
  The current level of evidence is not yet high enough to recommend pharmacogenetic personalization of immunosuppressive regimens in transplant recipients. The prevention of cellular toxicity associated with local metabolism or transport, which cannot be addressed by routine monitoring, is worth investigating further.
authors: INSERM, UMR-S850, Limoges, France.
authors: Nicolas
authors: N
authors: Picard
authors: Pierre
authors: P
authors: Marquet
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D065095:Calcineurin Inhibitors; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000633:toxicity; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D007168:IMP Dehydrogenase / Q000235:genetics; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D009173:Mycophenolic Acid / Q000493:pharmacokinetics / Q000627:therapeutic use; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000187:drug effects; D016032:Randomized Controlled Trials as Topic; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D016896:Treatment Outcome; D000090264:UDP-Glucuronosyltransferase 1A9
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D007168:IMP Dehydrogenase; C488211:IMPDH1 protein, human; D051544:Cytochrome P-450 CYP3A; D014453:Glucuronosyltransferase; D000090264:UDP-Glucuronosyltransferase 1A9; D058570:TOR Serine-Threonine Kinases; D009173:Mycophenolic Acid