Evaluation of 1b-hydroxylation of deoxycholic acid as a non-invasive urinary biomarker of cyp3a activity in the assessment of inhibition-based drug–drug interaction in healthy volunteers

Abstract

In this study, we aimed to evaluate the utility of endogenous 1B-hydroxy-deoxycholic acid/total deoxycholic acid ratio (1B-OH-DCA/ToDCA) in spot urine as a surrogate marker of cytochrome P450 3A (CYP3A) activity in the assessment inhibition-based drug–drug interactions in healthy volunteers. This was accomplished through an open-label, three-treatment parallel-arm study in healthy male volunteers from Zimbabwe. Each group received itraconazole (ITZ, 100 mg once daily, n = 10), fluconazole (FKZ, 50 mg once daily, n = 9), or alprazolam (APZ, 1 mg once daily, n = 8) orally. Midazolam (MDZ), dosed orally and intravenously, was used as a comparator to validate the exploratory measures of CYP3A activity and the effects of known inhibitors. Urinary metabolic ratios of 1B-OH-DCA/ToDCA before and after CYP3A inhibitor treatment showed a similar magnitude of inhibitory effects of the three treatments as that measured by oral MDZ clearance. The maximum inhibition effect of a 75% reduction in the 1B-OH-DCA/ToDCA ratio compared to the baseline was achieved in the ITZ group following six once-daily doses of 100 mg. The correlations of the two markers for CYP3A inhibitor treatment were significant (rs = 0.53, p < 0.01). The half-life of urinary endogenous 1B-OH-DCA/ToDCA was estimated as four days. These results suggested that 1B-OH-DCA/ToDCA in spot urine is a promising convenient, non-invasive, sensitive, and relatively quickly responsive endogenous biomarker that can be used for CYP3A inhibition-based drug–drug interaction in clinical studies.