The 1β-Hydroxy-Deoxycholic Acid to Deoxycholic Acid Urinary Metabolic Ratio: Toward a Phenotyping of CYP3A Using an Endogenous Marker?

Gaëlle Magliocco,Youssef Daali,Marija Bosilkovska,Jules Desmeules,Aurélien Thomas

doi:10.3390/jpm11020150

Abstract

In this study, we assessed the potential use of the 1β-hydroxy-deoxycholic acid (1β-OH-DCA) to deoxycholic acid (DCA) urinary metabolic ratio (UMR) as a CYP3A metric in ten male healthy volunteers. Midazolam (MDZ) 1 mg was administered orally at three sessions: alone (control session), after pre-treatment with fluvoxamine 50 mg (12 h and 2 h prior to MDZ administration), and voriconazole 400 mg (2 h before MDZ administration) (inhibition session), and after a 7-day pre-treatment with the inducer rifampicin 600 mg (induction session). The 1β-OH-DCA/DCA UMR was measured at each session, and correlations with MDZ metrics were established. At baseline, the 1β-OH-DCA/DCA UMR correlated significantly with oral MDZ clearance (r = 0.652, p = 0.041) and Cmax (r = −0.652, p = 0.041). In addition, the modulation of CYP3A was reflected in the 1β-OH-DCA/DCA UMR after the intake of rifampicin (induction ratio = 11.4, p < 0.01). During the inhibition session, a non-significant 22% decrease in 1β-OH-DCA/DCA was observed (p = 0.275). This result could be explained by the short duration of CYP3A inhibitors intake fixed in our clinical trial. Additional studies, particularly involving CYP3A inhibition for a longer period and larger sample sizes, are needed to confirm the 1β-OH-DCA/DCA metric as a suitable CYP3A biomarker.

Highlights

Macrolide antibiotics, calcium channel blockers, immunosuppressants, benzodiazepines, and many other compounds are metabolized by the cytochrome P450 3A (CYP3A) enzymes [1]
The magnitude of CYP3A induction reflected by the endogenous 1β-OH-deoxycholic acid (DCA)/DCA urinary metabolic ratio (UMR) was lower compared to oral MDZ CL but higher than plasma 1-OH-MDZ/MDZ MR at 1 h
The greater inter-individual variability observed in the endogenous UMR 1β-OH-DCA/DCA compared to MDZ metrics must be considered with caution and needs to be assessed in future studies with sufficient sample sizes

Summary

Introduction

Calcium channel blockers, immunosuppressants, benzodiazepines, and many other compounds are metabolized by the cytochrome P450 3A (CYP3A) enzymes [1]. It is estimated that approximately 30% of all marketed drugs are eliminated through this subfamily [1]. The metabolism of CYP3A substrates may be largely affected by the important pharmacokinetic variability of these enzymes’ function, leading to serious therapeutic complications [2,3]. Drug–drug interactions are a major cause of variability in CYP3A activity [1]. CYP3A can be induced by ligands that bind to the nuclear receptors. PXR and CAR, reducing the drug levels [4]. A number of endogenous and exogenous compounds can inhibit CYP3A activity, increasing the drug concentrations [5]

Objectives

Methods

Results

Discussion

Conclusion