PT - JOURNAL ARTICLE AU - Linda Björkhem-Bergman AU - Tobias Bäckström AU - Hanna Nylén AU - Yuko Rönquist-Nii AU - Eva Bredberg AU - Tommy B. Andersson AU - Leif Bertilsson AU - Ulf Diczfalusy TI - Comparison of Endogenous 4<em>β</em>-Hydroxycholesterol with Midazolam as Markers for CYP3A4 Induction by Rifampicin AID - 10.1124/dmd.113.052316 DP - 2013 Aug 01 TA - Drug Metabolism and Disposition PG - 1488--1493 VI - 41 IP - 8 4099 - http://dmd.aspetjournals.org/content/41/8/1488.short 4100 - http://dmd.aspetjournals.org/content/41/8/1488.full SO - Drug Metab Dispos2013 Aug 01; 41 AB - CYP3A4, considered the most important enzyme in drug metabolism, is often involved in drug-drug interactions. When developing new drugs, appropriate markers for detecting CYP3A4 induction are needed. Our study compared endogenously formed 4β-hydroxycholesterol with the midazolam clearance in plasma and the 6β-hydroxycortisol/cortisol ratio in urine as markers for CYP3A4 induction. To this end, 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) via the estimated midazolam clearance, the 4β-hydroxycholesterol ratio (both P &lt; 0.01), and the 6β-hydroxycortisol ratio (P &lt; 0.05). For the three dosing groups (10, 20, and 100 mg), the median fold induction from baseline was 2.0, 2.6, and 4.0 for the estimated midazolam clearance; 1.3, 1.6, and 2.5 for the 4β-hydroxycholesterol/cholesterol ratio; and 1.7, 2.9, and 3.1 for the 6β-hydroxycortisol/cortisol ratio. In conclusion, the 4β-hydroxycholesterol ratio is 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.