Impact of POR*28 on the clinical pharmacokinetics of CYP3A phenotyping probes midazolam and erythromycin

Laure Elens, Annemieke Nieuweboer, SJ Clarke, KA Charles, Anne-joy Graan, V Haufroid, Teun Gelder, RHJ Mathijssen, Ron van Schaik

Research output: Contribution to journalArticleAcademicpeer-review

29 Citations (Scopus)


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. Materials and 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. Conclusion 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. Pharmacogenetics and Genomics 23:148-155 (c) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
Original languageUndefined/Unknown
Pages (from-to)148-155
Number of pages8
JournalPharmacogenetics Genomics
Issue number3
Publication statusPublished - 2013

Cite this