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

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.

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Faculty of 1000 evaluation for Lack of a clinically significant drug-drug interaction in healthy volunteers between the HCV protease inhibitor boceprevir and the HIV integrase inhibitor raltegravir.

F1000 - Post-publication peer review of the biomedical literature ◽

10.3410/f.717958759.793470403 ◽

2013 ◽

Author(s):

Glenn Tillotson

Keyword(s):

Drug Interaction ◽

Protease Inhibitor ◽

Healthy Volunteers ◽

Integrase Inhibitor ◽

Hiv Integrase ◽

Hcv Protease ◽

Drug Drug Interaction ◽

Clinically Significant

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Lack of Clinically Relevant Drug–Drug Interaction Between Empagliflozin, a Sodium Glucose Cotransporter 2 Inhibitor, and Verapamil, Ramipril, or Digoxin in Healthy Volunteers

Clinical Therapeutics ◽

10.1016/j.clinthera.2013.02.015 ◽

2013 ◽

Vol 35 (3) ◽

pp. 226-235 ◽

Cited By ~ 19

Author(s):

Sreeraj Macha ◽

Regina Sennewald ◽

Peter Rose ◽

Katja Schoene ◽

Sabine Pinnetti ◽

...

Keyword(s):

Drug Interaction ◽

Healthy Volunteers ◽

Sodium Glucose Cotransporter ◽

Drug Drug Interaction

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In vitro Measurement and In vivo Prediction of Time-Dependent Inhibitory Effects of Three Tyrosine Kinase Inhibitors on CYP3A Activity

Current Drug Metabolism ◽

10.2174/1389200222666210902130319 ◽

2021 ◽

Vol 22 ◽

Author(s):

Liyan Wang ◽

Tingting Zhao ◽

Yunxiang Wang ◽

Banglian Hu ◽

Jianfei Tao ◽

...

Keyword(s):

Drug Interaction ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Kinase Inhibitors ◽

Liver Microsomes ◽

Inhibitory Effect ◽

Cyp3a Activity ◽

Drug Drug Interaction ◽

Inhibitory Potential

Background: Imatinib, sunitinib, and gefitinib are the three most common tyrosine kinase inhibitors (TKIs). However, their quantitative drug-drug interaction potentials In vivo and the relationship between their structure and inhibitory activity remain unknown. Objective: This study aimed to investigate the potential drug-drug interaction risk of three TKIs based on CYP3A. Methods: 6β-Hydroxylated testosterone formation was selected to probe the CYP3A activity in human liver microsomes. Molecular docking simulation was performed to explore the potential structural alerts. Results: Imatinib exhibited the strongest inhibitory effect towards CYP3A, while the inhibitory potential of gefitinib and sunitinib were comparable to each other but weaker than imatinib. IC50 shift assays demonstrated that the inhibitory potential of all three TKIs was significantly increased after a 30-min preincubation with NADPH. The KI and Kinact values of imatinib, sunitinib, and gefitinib were 3.75 μM and 0.055 min–1, 1.96 μM and 0.037 min–1, and 9.94 μM and 0.031 min–1, respectively. IVIVE results showed that there was a 1.3- to 43.1-fold increase in the AUC of CYP3A-metabolizing drugs in the presence of the TKIs. Conclusion: All three TKIs exhibited a typical irreversible inhibitory effect towards CYP3A. The presence of more N-heterocycles and the resulting better binding confirmation of imatinib may have been responsible for its stronger inhibitory effect than sunitinib and gefitinib. Therefore, caution should be taken when CYP3A-metabolizing drugs are co-administrated with imatinib, sunitinib, or gefitinib.

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