title: Quinine compared to 4β-hydroxycholesterol and midazolam as markers for CYP3A induction by rifampicin.
abstract: When developing new drugs appropriate markers for detecting induction and inhibition of cytochrome P450 3A enzymes (CYP3A) are needed. The aim of the present study was to evaluate the quinine/3-hydroxyquinine metabolic ratio (quinine MR) with other suggested markers for CYP3A induction: endogenously formed 4β-hydroxycholesterol, midazolam clearance in plasma and the 6β-hydroxycortisol/cortisol ratio in urine. We have previously performed a clinical trial in which 24 healthy subjects were randomized to take 10, 20 or 100 mg daily doses of rifampicin for 14 days (n = 8 in each group) to achieve a low and moderate CYP3A induction. In newly analyzed data from this study we can show that the quinine MR could detect CYP3A-induction even at the lowest dose of rifampicin (10 mg) (p < 0.01), comparable to a 4β-hydroxycholesterol/cholesterol ratio and midazolam clearance. The median fold-induction for the quinine MR compared to baseline was 1.7, 1.8 and 2.6 for the three dosing groups (10, 20 and 100 mg). In conclusion, in this study the quinine MR was comparable to midazolam clearance as a measure of CYP3A activity but easier to determine since only a single blood sample needs to be drawn.
authors: Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge.
authors: Linda
authors: L
authors: Björkhem-Bergman
authors: Tobias
authors: T
authors: Bäckström
authors: Hanna
authors: H
authors: Nylén
authors: Yuko
authors: Y
authors: Rönquist-Nii
authors: Eva
authors: E
authors: Bredberg
authors: Tommy B
authors: TB
authors: Andersson
authors: Leif
authors: L
authors: Bertilsson
authors: Ulf
authors: U
authors: Diczfalusy
mesh_terms: D015415:Biomarkers / Q000097:blood / Q000652:urine; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065701:Cytochrome P-450 CYP3A Inducers / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D064368:Healthy Volunteers; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives* / Q000652:urine*; D006888:Hydroxycholesterols / Q000097:blood*; D008874:Midazolam / Q000097:blood*; D011802:Quinidine / Q000031:analogs & derivatives / Q000097:blood; D011803:Quinine / Q000097:blood*; D012293:Rifampin / Q000494:pharmacology*
chemical_list: D015415:Biomarkers; D065701:Cytochrome P-450 CYP3A Inducers; D006888:Hydroxycholesterols; C013569:3-hydroxyquinidine; C001380:6 beta-hydroxycortisol; D011803:Quinine; D051544:Cytochrome P-450 CYP3A; D011802:Quinidine; D008874:Midazolam; D012293:Rifampin; D006854:Hydrocortisone