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

OBJECTIVE

P450 oxidoreductase (POR) is essential for cytochrome P450 (CYP) activity in humans. The POR28 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 POR28 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 POR28, CYP3A422 and CYP3A5*3.

RESULTS

In patients expressing CYP3A5, POR28 carriers showed 45% lower midazolam metabolic ratios compared with POR1/1 patients (P<0.001). This is in line with a lower CYP3A5 activity toward midazolam for POR28 carriers. In CYP3A5 nonexpressers, POR28 had no influence on midazolam pharmacokinetics. For erythromycin, POR28 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.