Urinary 6?-hydroxycortisol: a validated test for evaluating drug induction or drug inhibition mediated through CYP3A in humans and in animals

Abstract

6beta-Hydroxycortisol (6beta-OHF) urinary excretion has, for a long time, been considered a marker of drug induction and, more recently, of drug inhibition in humans and in laboratory animals, but its specificity is still under debate. In this work, we review 277 papers devoted to 6beta-OHF urinary excretion. We have evaluated factors that could modify 6beta-OHF excretion and, thus, could explain contradictory results. We have examined the effect of the analytical techniques on physiological values. Intra- and inter-individual variability and the effect of circadian rhythms on urinary excretion of 6beta-OHF as well as cortisol and 17-hydroxycorticosteroids have been evaluated. We also give an overview of drugs that induce, inhibit or have no effect on 6beta-OHF. For inducing and inhibiting drugs, we calculated the ranges of variation of 6beta-OHF excretion from the results indicated in the different papers. This work was done for well-known inducers, such as anticonvulsants, but also for other inducing or inhibiting drugs found in the literature. The time-course of variation in 6beta-OHF excretion when different drugs are co-administered was also investigated. The potential relationship between cytochrome P(450) 3A4 (CYP3A4) polymorphism and 6beta-OHF excretion was studied. Finally, the interest of 6beta-OHF urinary excretion was compared with that of other tests proposed to measure CYP3A4 activity. This review demonstrates that 6beta-OHF urinary excretion is a good test to evaluate drug-metabolising enzyme inducing or inhibiting properties of drugs when the subjects are their own controls, but this test is not reliable enough to measure actual CYP3A4 activity.

Prediction of tacrolimus metabolism and dosage requirements based on CYP3A4 phenotype and CYP3A5*3 genotype in Chinese renal transplant recipients

“…As a complementary or alternative strategy, determination of a patient's CYP3A4 phenotype may help to overcome the limitations of genetic assays and optimize Tac dosage regimens. Currently, the ratio of 6β-hydroxycortisol to free cortisol (6β-OHF/F) in urine is thought to be a useful marker of both the induction and the inhibition of hepatic CYP3A4 activity [8] . The interconversion of cortisol (F) to cortisone (E) and 6β-hydroxycortisol (6β-OHF) to 6β-hydroxycortisone (6β-OHE) by 11β-hydroxysteroid dehydrogenase (11β-HSD) plays an important role in cortisol metabolism; thus, using cortisol as a CYP3A4 phenotyping probe may be confounded due to the regulation of cortisol feedback [9,10] .…”

No relevant effect of ursodeoxycholic acid on cytochrome P450 3A metabolism in primary biliary cirrhosis

“…We analyzed CYP3A metabolism by (1) CYP3A-dependent 25 pharmacokinetics of oral budesonide, a glucocorticosteroid recently being suggested for combined medical treatment of early-stage PBC, 26,27 and by (2) urinary 6␤-hydroxycortisol, a noninvasive, validated marker of CYP3A induction. 28 (2) an alkaline phosphatase or ␥-glutamyltransferase level of more than 1.5-fold the upper limit of normal at initial diagnosis, and (3) histologically proven noncirrhotic liver disease compatible with PBC stages I-II within 5 years before inclusion and no morphological signs of portal hypertension on abdominal ultrasound at study entry. Exclusion criteria in patients and healthy volunteers were (1) cardiac, renal, gastrointestinal, and other findings that may interfere with the tolerability or pharmacokinetics of the study drugs; (2) excessive alcohol consumption (Ͼ35 g/d in men and Ͼ25 g/d in women); (3) smoking in healthy volunteers or heavy smoking in patients (Ͼ10 cigarettes/ d); (4) human immunodeficiency virus or hepatitis C virus infection; (5) administration of glucocorticosteroids within 6 weeks before the first study day; (6) use of drugs during the 4 weeks before the first administration or during the trial that may influence biotransformation of budesonide 29 ; (7) intake of grapefruit or grapefruit juice within 1 week before administration of the first study drug; and (8) administration of agents interfering with gastrointestinal absorption and motility within the 3 days before the start of the study.…”

Evaluation of CYP3A activity in humans using three different parameters based on endogenous cortisol metabolism

“…However, there were no significant correlations between any of these measures and CYP3A activity (indicated by the secretion and metabolism of cortisol). It is now known that cortisol is produced by the adrenal cortex, and its secretion exhibits a circadian rhythm; the highest levels are secreted between 08:00 and 12:00 and the lowest levels are released at midnight [7] . The pathway underlying cortisol metabolism in humans is complex.…”

“…It is also worth noting that CYP3A consists of at least three isoforms: CYP3A4, CYP3A5, and CYP3A7. Although CYP3A5 may also have played a role here, the relative contribution of each of these isoforms to cortisol metabolism has not been completely elucidated [7] .…”

“…It has been suggested that the urinary ratio of 6β-OHF/F is also a useful marker of both the induction and the inhibition of hepatic CYP3A activity [7] . However, this measure does not appear to be an accurate marker of the pharmacokinetic properties of other substrates of CYP3A, such as the well-known probe drug MDZ and erythromycin [8][9][10] .…”