title: Intraindividual and interindividual variabilities in endogenous cortisol 6β-hydroxylation clearance as an index for in vivo CYP3A phenotyping in humans.
abstract: This study was designed to evaluate the in vivo activity of cytochrome P450 3A (CYP3A) in 49 healthy Japanese subjects aged 22-58 years using endogenous cortisol 6β-hydroxylation clearance [CLm(6β)], a novel biomarker for CYP3A phenotyping. CLm(6β) in the 49 healthy subjects was 2.40 ± 0.79 ml/min with an approximately 4-fold interindividual variability of CYP3A activity. The mean clearance in the 24 women was 2.50 ± 0.89 ml/min; the value in the women was higher than in the 25 men (2.30 ± 0.69 ml/min) by approximately 9%. We also measured the change of CLm(6β) in 14 healthy subjects in the morning at 10:00-12:00 every 2 or 3 days over a period of 36-53 days and observed a 1.5-fold to 3.4-fold day-to-day intraindividual variability in the CYP3A activity. The mean value for CLm(6β) in each subject for 36-53 days was 2.54 ± 0.76 ml/min (n = 14). We also evaluated the CLm(6β) every 2 hours from 8:00-20:00 in 26 healthy subjects. The within-day intraindividual clearance variability was 1.1-fold to 2.5-fold (2.45 ± 0.91 ml/min, n = 26). No characteristic diurnal rhythms were observed in the in vivo activity of CYP3A.
authors.affiliation: School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Shibasaki
authors.forename: Kaori
authors.initials: K
authors.lastname: Hosoda
authors.forename: Mari
authors.initials: M
authors.lastname: Goto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Suzuki
authors.forename: Akitomo
authors.initials: A
authors.lastname: Yokokawa
authors.forename: Kazuo
authors.initials: K
authors.lastname: Ishii
authors.forename: Takashi
authors.initials: T
authors.lastname: Furuta
mesh_terms: D000328:Adult; D044466:Asian People; D015415:Biomarkers / Q000097:blood; D001711:Biotransformation; D002940:Circadian Rhythm; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives* / Q000097:blood; D006900:Hydroxylation; D007564:Japan; D007700:Kinetics; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010641:Phenotype; D012737:Sex Factors; D013379:Substrate Specificity; D055815:Young Adult
chemical_list: D015415:Biomarkers; C001380:6 beta-hydroxycortisol; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D006854:Hydrocortisone