RT Journal Article
SR Electronic
T1 EVIDENCE FOR THE VALIDITY OF CORTISOL 6β-HYDROXYLATION CLEARANCE AS A NEW INDEX FOR IN VIVO CYTOCHROME P450 3A PHENOTYPING IN HUMANS
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1283
OP 1287
DO 10.1124/dmd.31.11.1283
VO 31
IS 11
A1 Takashi Furuta
A1 Atsushi Suzuki
A1 Chieko Mori
A1 Hiromi Shibasaki
A1 Akitomo Yokokawa
A1 Yasuji Kasuya
YR 2003
UL http://dmd.aspetjournals.org/content/31/11/1283.abstract
AB This study uses stable isotope methodology to evaluate the validity of 6β-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 6β-hydroxycortisol to cortisol (6β-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 6β-hydroxylation of cortisol. Plasma concentrations of labeled cortisol and urinary excreted amounts of labeled cortisol and 6β-OHF were analyzed by gas chromatography-mass spectrometry simultaneously with their endogenous counterparts. There was a good correlation between endogenous and exogenous 6β-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 6β-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 6β-OHF/F, a function of 6β-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 6β-hydroxylation clearance of endogenous cortisol but not by the urinary ratio 6β-OHF/F. The American Society for Pharmacology and Experimental Therapeutics