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Article

Evaluation of 1β-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

1
Drug Metabolism and Pharmacokinetics, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, 431 83 Gothenburg, Sweden
2
Department of Pharmaceutical Medicine, African Institute of Biomedical Science and Technology (AiBST), Block C, Wilkins Hospital Complex, Harare, Zimbabwe
3
Division of Clinical Pharmacology-C1:68, Department of Laboratory Medicine at Karolinska Institutet, Karolinska University Hospital, SE-141 86 Stockholm, Sweden
4
Division of Clinical Chemistry, Department of Laboratory Medicine at Karolinska Institutet, Karolinska University Hospital (Huddinge), SE-141 86 Stockholm, Sweden
*
Author to whom correspondence should be addressed.
These authors made equal contributions.
Academic Editor: Gianluca Ingrosso
J. Pers. Med. 2021, 11(6), 457; https://doi.org/10.3390/jpm11060457
Received: 13 April 2021 / Revised: 3 May 2021 / Accepted: 8 May 2021 / Published: 24 May 2021
(This article belongs to the Special Issue Stereotactic Body Radiotherapy)
In this study, we aimed to evaluate the utility of endogenous 1β-hydroxy-deoxycholic acid/total deoxycholic acid ratio (1β-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 1β-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 1β-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 1β-OH-DCA/ToDCA was estimated as four days. These results suggested that 1β-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. View Full-Text
Keywords: CYP3A; biomarker; human; deoxycholic acid; 1β-hydroxy-deoxycholic acid; urine; midazolam; drug–drug interaction CYP3A; biomarker; human; deoxycholic acid; 1β-hydroxy-deoxycholic acid; urine; midazolam; drug–drug interaction
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MDPI and ACS Style

Li, X.-Q.; Thelingwani, R.S.; Bertilsson, L.; Diczfalusy, U.; Andersson, T.B.; Masimirembwa, C. Evaluation of 1β-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. J. Pers. Med. 2021, 11, 457. https://doi.org/10.3390/jpm11060457

AMA Style

Li X-Q, Thelingwani RS, Bertilsson L, Diczfalusy U, Andersson TB, Masimirembwa C. Evaluation of 1β-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. Journal of Personalized Medicine. 2021; 11(6):457. https://doi.org/10.3390/jpm11060457

Chicago/Turabian Style

Li, Xue-Qing; Thelingwani, Roslyn S.; Bertilsson, Leif; Diczfalusy, Ulf; Andersson, Tommy B.; Masimirembwa, Collen. 2021. "Evaluation of 1β-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" J. Pers. Med. 11, no. 6: 457. https://doi.org/10.3390/jpm11060457

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