title: Impact of POR*28 on the clinical pharmacokinetics of CYP3A phenotyping probes midazolam and erythromycin.
abstract: OBJECTIVE
  P450 oxidoreductase (POR) is essential for cytochrome P450 (CYP) activity in humans. The POR*28 allele (A503V) has been shown to impact on in-vitro CYP-mediated metabolism, including CYP3A isoenzymes. The aim of the present study was to determine the in vivo impact of the POR*28 allele on the pharmacokinetics of the classic CYP3A phenotyping probes midazolam and erythromycin. Whereas midazolam is metabolized by both CYP3A4 and CYP3A5, erythromycin is exclusively oxidized by CYP3A4.
  
  
  METHODS
  To assess CYP3A activity, 108 cancer patients received midazolam and 45 others underwent the erythromycin breath test. Patients were genotyped for POR*28, CYP3A4*22 and CYP3A5*3.
  
  
  RESULTS
  In patients expressing CYP3A5, POR*28 carriers showed 45% lower midazolam metabolic ratios compared with POR*1/*1 patients (P<0.001). This is in line with a lower CYP3A5 activity toward midazolam for POR*28 carriers. In CYP3A5 nonexpressers, POR*28 had no influence on midazolam pharmacokinetics. For erythromycin, POR*28 carriership did not influence its metabolism.
  
  
  CONCLUSIONS
  Our data show that the POR*28 allele is associated with a lower in vivo CYP3A5 activity, but has no effects on CYP3A4-mediated erythromycin and midazolam metabolism.
authors: Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors: Laure
authors: L
authors: Elens
authors: Annemieke J M
authors: AJ
authors: Nieuweboer
authors: Stephen J
authors: SJ
authors: Clarke
authors: Kellie A
authors: KA
authors: Charles
authors: Anne-Joy M
authors: AJ
authors: de Graan
authors: Vincent
authors: V
authors: Haufroid
authors: Teun
authors: T
authors: van Gelder
authors: Ron H J
authors: RH
authors: Mathijssen
authors: Ron H N
authors: RH
authors: van Schaik
mesh_terms: D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004917:Erythromycin / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics*; D010641:Phenotype
chemical_list: D004917:Erythromycin; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam