Evidence for the validity of cortisol 6 beta-hydroxylation clearance as a new index for in vivo cytochrome P450 3A phenotyping in humans.
This study uses stable isotope methodology to evaluate the validity of 6beta-hydroxylation clearance of endogenous cortisol as a new index for in vivo CYP3A phenotyping in humans. Important factors contradictory to the use of a conventional index of urinary ratio of 6beta-hydroxycortisol to cortisol (6beta-OHF/F) to evaluate in vivo CYP3A activity are also discussed. Stable isotopically labeled cortisol (3-5 mg) was orally administered to three healthy adult subjects to accurately determine the fractional metabolic clearance specific for the 6beta-hydroxylation of cortisol. Plasma concentrations of labeled cortisol and urinary excreted amounts of labeled cortisol and 6beta-OHF were analyzed by gas chromatography-mass spectrometry simultaneously with their endogenous counterparts. There was a good correlation between endogenous and exogenous 6beta-hydroxylation clearances in the three subjects tested (r = 0.7733, 0.9112, and 0.9534 for 2-, 4-, and 6- to 8-h urine collection periods, respectively). This strongly suggests that the endogenous 6beta-hydroxylation clearance can be used as an appropriate index for phenotyping the in vivo CYP3A activity. Furthermore, observed intra- (2.1- to 4.6-fold) and interindividual variabilities (ca. 5-fold) in the labeled cortisol renal clearance suggest that the urinary ratio 6beta-OHF/F, a function of 6beta-hydroxylation clearance and renal clearance of cortisol, does not always reflect the in vivo CYP3A activity. When a macrolide antibiotic, clarithromycin, was administered to a healthy volunteer in a dose of 200 mg every 12 h for 6 days, the inhibitory effects of clarithromycin on the in vivo CYP3A activity were clearly seen by the 6beta-hydroxylation clearance of endogenous cortisol but not by the urinary ratio 6beta-OHF/F.
Department of Medicinal Chemistry and Clinical Pharmacy, School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. furutat@ps.toyaku.ac.jp
Takashi
T
Furuta
Atsushi
A
Suzuki
Chieko
C
Mori
Hiromi
H
Shibasaki
Akitomo
A
Yokokawa
Yasuji
Y
Kasuya
D000328:Adult; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D006900:Hydroxylation; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology; D010641:Phenotype
C001380:6 beta-hydroxycortisol; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D006854:Hydrocortisone