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

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 C_max (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.

Keywords: CYP3A; CYP450; bile acid; biomarker; phenotyping.

Figure 1

Study timeline. Midazolam 1 mg, as part of the Geneva cocktail, was orally administered on days 1, 8, and 22. Fluvoxamine 50 mg was administered 12 h and 2 h before the administration of midazolam (inhibition session). Voriconazole 400 mg was administered 2 h before the administration of midazolam (inhibition session). Rifampicin 600 mg was administered once daily for seven days until the evening before the administration of midazolam (induction session).

Figure 2

Oral midazolam clearance in ten mal volunteers who received 1 mg midazolam orally at baseline and after (a) inhibition by voriconazole and fluvoxamine, and (b) induction by rifampicin. Error bars represent the standard deviations of log-transformed oral midazolam clearance and mean values are displayed with a circle. CL, clearance; MDZ, midazolam. ** p < 0.01

Figure 3

Eight-hour 1β-hydroxy-deoxycholic acid/deoxycholic acid individual urinary metabolic ratios at baseline and after (a) the inhibition by voriconazole and fluvoxamine, and (b) induction by rifampicin. Error bars represent the standard deviations of log-transformed 1β-hydroxy-deoxycholic acid (1β-OH-DCA/DCA) and mean values are displayed with a circle. 1β-OH-DCA/DCA, 1β-hydroxy-deoxycholic acid/deoxycholic acid. ** p < 0.01

Figure 4

Correlation between log-transformed 1β-hydroxy-deoxycholic acid/deoxycholic acid urinary metabolic ratio and oral midazolam clearance after (a) the administration of midazolam alone and after (b) the administration of midazolam alone and after pretreatment with voriconazole/fluvoxamine or rifampicin. Black circles, baseline; CYP3A4-inhibited phase, red square; CYP3A4-induced phase, blue triangles. 1β-OH-DCA/DCA, 1β-hydroxy-deoxycholic acid/deoxycholic acid; CL, clearance; MDZ, midazolam.