Circadian variation of the urinary 6beta-hydroxycortisol to cortisol ratio that would reflect hepatic CYP3A activity.
OBJECTIVE
Chronopharmacokinetics of drugs metabolized by cytochrome P450 3A (CYP3A) has been reported recently; however, little is studied on intra-individual circadian variation in CYP3A activity in human. The aim of this study was to assess the intra-individual diurnal variation and day-to-day variation of the urinary 6beta-hydroxycortisol to cortisol ratio, a noninvasive index of human CYP3A activity.


METHODS
Urine samples from ten healthy Japanese men were collected over four time intervals (0900 hours to 1300 hours, 1300 hours to 1700 hours, 1700 hours to 2100 hours and 2100 hours to 0900 hours) on days 1, 5 and 14 to verify diurnal variation, and 24-h urine was collected to study day-to-day variation over 2 weeks. Urinary 6beta-hydroxycortisol and cortisol were determined by means of high-performance liquid chromatography/atmospheric pressure chemical ionization-mass spectrometry.


RESULTS
The ratio of urinary 6beta-hydroxycortisol to cortisol exhibited noteworthy diurnal variation intra-individually; 2.8-fold on average. However, day-do-day intra-individual variation of the ratio was not observed over 2 weeks; the coefficient of variation was 11.9 +/- 3.0%.


CONCLUSIONS
The result indicates that imprudent use of random urine has a great risk of false evaluation in assessment of the 6beta-hydroxycortisol to cortisol ratio and that the ratio in 24-h urine samples provides a more robust measure of the inter-individual difference of this metabolic ratio, which to a certain but not complete extent represents the CYP3A activity.
Ohno
M
M
Department of Clinical Evaluation of Medicines and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.
Yamaguchi
I
I
Ito
T
T
Saiki
K
K
Yamamoto
I
I
Azuma
J
J
D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases; D002851:Chromatography, High Pressure Liquid; D002940:Circadian Rhythm; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives* / Q000652:urine*; D008099:Liver / Q000201:enzymology*; D008297:Male; D013058:Mass Spectrometry; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D013997:Time Factors
C001380:6 beta-hydroxycortisol; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D006854:Hydrocortisone