1: Int J Clin Pharmacol Ther  2001 Jul;39(7):293-9

Midazolam and cortisol metabolism before and after CYP3A induction in humans.

Eeckhoudt SL, Desager JP, Robert AR, Leclercq I, Verbeeck RK, Horsmans Y.

Unite de Pharmacocinetique, Metabolisme, Nutrition et Toxicologie, Ecole de
Sante Publique, Universite catholique de Louvain, Brussels, Belgium.

INTRODUCTION: CYP3A is responsible for the metabolism of numerous endogenous and
exogenous compounds. Several substrates of CYP3A have been investigated to
assess the CYP3A-metabolizing capacity of an individual in an attempt to predict
the rate of metabolism of other CYP3A substrates. Two such tests of CYP3A
activity are the midazolam plasma clearance after its intravenous administration
and the 6beta-OH cortisol urinary ratio. Possible correlations between these 2
tests were investigated before and after treatment with rifampin in a group of
healthy volunteers. METHODS: Pharmacokinetic parameters of midazolam and
6beta-OH cortisol urinary ratio were evaluated in 8 volunteers before and after
6 days treatment with rifampin, a potent inducer of CYP3A, and after cessation
of rifampin treatment. RESULTS: Midazolam systemic clearance and the 6beta-OH
cortisol urinary ratio were significantly higher at Days 7 and 10 than at Day 0.
There was a strong positive correlation between these 2 parameters (r = 0.70, p
< 0.001). In contrast, no correlation was observed between the ratio of the AUCs
of 1'-OH midazolam vs. midazolam (AUC0-1(1'-OH)/AUC0-t(MDZ)) or the ratio of
plasma concentration of 1'-OH midazolam vs. midazolam (C30 min(1'-OH)/C30
min(MDZ)) and the 6beta-OH cortisol urinary ratio (r = 0.05, p = 0.82; r = 0.04,
p = 0.88, respectively). Considering only data obtained before or after
treatment with rifampin, however, no correlation was observed between midazolam
systemic clearance and the 6beta-OH cortisol urinary ratio. CONCLUSIONS: These
data demonstrate that there is a strong positive correlation between systemic
midazolam clearance and 6beta-OH cortisol urinary ratio before and after
induction. This suggests that the 6beta-OH cortisol urinary ratio test is a
non-invasive alternative to the use of systemic midazolam clearance for
monitoring the time-course of CYP3A induction.

Publication Types:
Clinical Trial

PMID: 11471773 [PubMed - indexed for MEDLINE]