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Comparison of Endogenous 4β-hydroxycholesterol with Midazolam as Markers for CYP3A4 Induction by Rifampicin.

Drug Metab Dispos. 2013 May 14;

Authors: Bjorkhem-Bergman L, Backstrom T, Nylen H, Ronquist-Nii Y, Bredberg E, Andersson TB, Bertilsson L, Diczfalusy U


Cytochrome P450 3A4 (CYP3A4) is considered the most important enzyme in drug metabolism and is often involved in drug-drug interactions. When developing new drugs appropriate markers for detecting CYP3A4-induction are needed. The aim of the present study was to compare the endogenously formed 4β-hydroxycholesterol with midazolam clearance in plasma and with 6β-hydroxycortisol / cortisol ratio in urine as markers for CYP3A4 induction. To do this we performed a clinical trial in which 24 healthy subjects were randomized to 10, 20 or 100 mg daily doses of rifampicin for 14 days (n=8 in each group) to achieve a low and moderate CYP3A4 induction. The CYP3A4-induction could be detected, even at the lowest dose of rifampicin (10 mg), by estimated midazolam clearance and 4β-hydroxycholesterol ratio (both p<0.01) and by 6β-hydroxycortisol ratio (p<0.05). The median fold-induction from baseline was 2.0, 2.6 and 4.0 for estimated midazolam clearance, 1.3, 1,6 and 2.5 for 4β-hydroxycholesterol / cholesterol ratio and 1.7, 2.9 and 3.1 for 6β-hydroxycortisol / cortisol ratio for the three dosing groups (10, 20 and 100 mg). In conclusion, 4β-hydroxycholesterol ratio was comparable to midazolam clearance as a marker of CYP3A4 induction and each may be used to evaluate CYP3A4-induction in clinical trials evaluating drug-drug interactions for new drugs.

PMID: 23674608 [PubMed - as supplied by publisher]