Published in
Lippincott, Williams & Wilkins, Pharmacogenetics and Genomics, 3(23), p. 148-155, 2013
DOI: 10.1097/fpc.0b013e32835dc113
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Impact of POR*28 on the Clinical Pharmacokinetics of CYP3A Phenotyping Probes Midazolam and Erythromycin
,
Annemieke J. M. Nieuweboer,
Anne-Joy M. de Graan,
Stephen J. Clarke,
Kellie A. Charles,
Teun van Gelder,
A.-J. M. De Graan,
Ron H. N. van Schaik,
Vincent Haufroid,
T. Van Gelder,
Ron H. J. Mathijssen,
13th International Congress of Therapeutic Drug Monitoring and Clinical Toxicology,
R. H. N. Van Schaik
Full text: Unavailable
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. 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