title: Comparison of endogenous 4β-hydroxycholesterol with midazolam as markers for CYP3A4 induction by rifampicin.
abstract: 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 < 0.01), and the 6β-hydroxycortisol ratio (P < 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.
authors.affiliation: Division of Clinical Pharmacology C1-68, Karolinska University Hospital, Huddinge, Karolinska Institutet, SE-141 86, Stockholm, Sweden. linda.bjorkhem-bergman@ki.se
authors.forename: Linda
authors.initials: L
authors.lastname: Björkhem-Bergman
authors.forename: Tobias
authors.initials: T
authors.lastname: Bäckström
authors.forename: Hanna
authors.initials: H
authors.lastname: Nylén
authors.forename: Yuko
authors.initials: Y
authors.lastname: Rönquist-Nii
authors.forename: Eva
authors.initials: E
authors.lastname: Bredberg
authors.forename: Tommy B
authors.initials: TB
authors.lastname: Andersson
authors.forename: Leif
authors.initials: L
authors.lastname: Bertilsson
authors.forename: Ulf
authors.initials: U
authors.lastname: Diczfalusy
mesh_terms: D000328:Adult; D015415:Biomarkers; D002784:Cholesterol / Q000097:blood; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis*; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives / Q000652:urine; D006888:Hydroxycholesterols / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008874:Midazolam / Q000493:pharmacokinetics*; D012293:Rifampin / Q000494:pharmacology*
chemical_list: D015415:Biomarkers; D006888:Hydroxycholesterols; C099828:cholest-5-ene-3,4-diol; C001380:6 beta-hydroxycortisol; D002784:Cholesterol; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam; D012293:Rifampin; D006854:Hydrocortisone