1β-Hydroxydeoxycholic Acid as an Endogenous Biomarker in Human Plasma for Assessment of CYP3A Clinical Drug-Drug Interaction Potential
4β-Hydroxycholesterol (4β-HC) in plasma has been used as a biomarker to assess CYP3A drug-drug interaction (DDI) potential during drug development. However, due to the long half-life and narrow dynamic range of 4β-HC, its use has been limited to the identification of CYP3A inducers, but not CYP3A in...
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Published in | Drug metabolism and disposition Vol. 52; no. 9; pp. 966 - 974 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
01.09.2024
|
Subjects | |
Online Access | Get full text |
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Summary: | 4β-Hydroxycholesterol (4β-HC) in plasma has been used as a biomarker to assess CYP3A drug-drug interaction (DDI) potential during drug development. However, due to the long half-life and narrow dynamic range of 4β-HC, its use has been limited to the identification of CYP3A inducers, but not CYP3A inhibitors. The formation of 1β-hydroxydeoxycholic acid (1β-OH DCA) from deoxycholic acid (DCA) is mediated by CYP3A, thus 1β-OH DCA can potentially serve as an alternative to 4β-HC for assessment of CYP3A DDI potential. To study this feasibility, we developed a sensitive LC-MS/MS method for the simultaneous quantitation of 1β-OH DCA and its glycine and taurine conjugates in human plasma with the LLOQ of 50 pg/mL, which enabled the quantitation of basal levels and further reduction. The method was applied to a DDI study to assess how 1β-OH DCA and its glycine and taurine conjugates would respond to CYP3A induction or inhibition. Rifampin induction resulted in an increase of 1β-OH DCA and its conjugates in plasma, with 6.8-, 7.8-, 8.3-, 10.3-fold increases of AUC
, AUC
, C
and mean concentrations for total 1β-OH DCA (total of all three forms), respectively. Importantly, inhibition with itraconazole resulted in notable reduction of these biomarkers, with 84%, 85%, 82%, 81% reductions of AUC
, AUC
, C
and mean concentrations for total 1β-OH DCA, respectively. This preliminary data demonstrates for the first time that total 1β-OH DCA in plasma has the potential to serve as a biomarker for CYP3A DDI assessment in early clinical development and may provide key advantages over 4β-HC.
We have reported the use of total 1β-Hydroxydeoxycholic Acid (1β-OH DCA) (sum of 1β-OH DCA and its glycine and taurine conjugates) plasma concentration as a biomarker for CYP3A activity. Itraconazole inhibition led to an 81-85% decrease of total 1β-OH DCA plasma exposures, while rifampin induction led to a 6.8-10.3 fold increase of total 1β-OH DCA plasma exposures. Using 1β-OH DCA exposures in plasma also provides benefit of allowing PK and biomarker assessment using the same matrix, thus simplify collection procedures. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0090-9556 1521-009X 1521-009X |
DOI: | 10.1124/dmd.124.001680 |