title: Impact of CYP3A5 genotype on tacrolimus versus midazolam clearance in renal transplant recipients: new insights in CYP3A5-mediated drug metabolism.
abstract: OBJECTIVE
  In vitro studies have identified both midazolam and tacrolimus as dual CYP3A4 and CYP3A5 substrates. In vivo; however, the CYP3A5 genotype has a marked impact on tacrolimus pharmacokinetics, whereas it seems not to affect midazolam pharmacokinetics. The aim of the current study was to explore this paradigm in a relevant clinical setting.
  
  
  METHODS
  A case-control study in 80 tacrolimus-treated renal transplant recipients comparing systemic and apparent oral midazolam clearance and tacrolimus pharmacokinetics in CYP3A5 expressers (CYP3A5*1 allele carriers) and CYP3A5 nonexpressers (CYP3A5*3/*3) was performed.
  
  
  RESULTS
  CYP3A5 expressers display an approximately 2.4-fold higher tacrolimus clearance as compared with CYP3A5 nonexpressers, whereas there are no differences in systemic and apparent oral midazolam clearance.
  
  
  CONCLUSIONS
  These data confirm that in vivo CYP3A5 plays an important role in tacrolimus metabolism, while its contribution to midazolam metabolism in a relevant study population is limited. Furthermore, these data suggest that midazolam is to be considered as a phenotypic probe for in vivo CYP3A4 activity rather than combined CYP3A4 and CYP3A5 activity.
authors.affiliation: Department of Nephrology & Renal Transplantation, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium.
authors.forename: Hylke
authors.initials: H
authors.lastname: de Jonge
authors.forename: Henriette
authors.initials: H
authors.lastname: de Loor
authors.forename: Krisitin
authors.initials: K
authors.lastname: Verbeke
authors.forename: Yves
authors.initials: Y
authors.lastname: Vanrenterghem
authors.forename: Dirk R J
authors.initials: DR
authors.lastname: Kuypers
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis / Q000235:genetics*; D015870:Gene Expression; D056726:Genetic Association Studies; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D016030:Kidney Transplantation; D008874:Midazolam / Q000008:administration & dosage* / Q000009:adverse effects; D008875:Middle Aged; D016559:Tacrolimus / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam; D016559:Tacrolimus