Itraconazole-Induced Increases in Gilteritinib Exposure Are Mediated by CYP3A and OATP1B
Abstract
:1. Introduction
2. Results
2.1. Contribution of CYP3A to the Interaction between Gilteritinib and Itraconazole
2.2. Interaction of Gilteritinib with OATP1B-Type Transporters
2.3. Contribution of OATP1B to the Interaction between Gilteritinib and Itraconazole
2.4. Impact of Itraconazole on Endogenous Biomarker of OATP1B Function
3. Discussion
4. Materials and Methods
4.1. Chemicals and Reagents
4.2. Transport Inhibition Assays
4.3. Competitive Counterflow Assays
4.4. Washout Assay
4.5. In Vivo Pharmacokinetic Studies
4.6. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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Mouse Genotype | Co-Treatment Dose (mg/kg) | Gilteritinib Cmax (ng/mL) | Gilteritinib AUC0–24h (ng ∗ h/mL) | Gilteritinib AUC Fold Increase |
---|---|---|---|---|
Wild-type FVB | None | 310 (±180) | 4650 (±960) | |
Wild-type FVB | Itraconazole (100) | 960 (±630) * | 11,480 (±4430) ** | 2.5 (vs. Vehicle) |
CYP3A(−/−) | None | 380 (±160) | 5990 (±1320) | 1.3 (vs. WT) |
CYP3A(−/−) | Itraconazole (100) | 430 (±130) | 5840 (±1520) | 0.97 (vs. Vehicle) |
Wild-type DBA/1J | None | 260 (±250) | 4550 (±2720) | |
OATP1B2(−/−) | None | 390 (±380) | 6160 (±2250) | 1.4 (vs. WT) |
OATP1B2(−/−) | None | 1430 (±540) | 17,840 (±5500) | |
OATP1B2(−/−) | Itraconazole (100) | 1350 (±1050) | 15,050 (±5930) | 0.84 (vs. Vehicle) |
Mouse Genotype | Treatment (Dose mg/kg) | CDCA-24G Cmax (ng/mL) | CDCA-24G AUC0–4h (ng ∗ h/mL) | CDCA-24G AUC Fold Increase |
---|---|---|---|---|
Wild-type FVB | None | 1.17 (±0.38) | 3.78 (±0.20) | |
Wild-type FVB | Itraconazole (100) | 1.84 (±0.60) * | 5.10 (±1.60) * | 1.3 (vs. WT) 1.5 (vs. CYP3A (−/−) + Itraconazole) |
CYP3A(−/−) | None | 1.02 (±0.36) | 3.35 (±1.10) | 0.9 (vs. WT) |
CYP3A(−/−) | Itraconazole (100) | 0.98 (±0.20) | 3.30 (±1.00) | 1 (vs. CYP3A(−/−)) 0.9 (vs. WT Alone) |
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Garrison, D.A.; Jin, Y.; Talebi, Z.; Hu, S.; Sparreboom, A.; Baker, S.D.; Eisenmann, E.D. Itraconazole-Induced Increases in Gilteritinib Exposure Are Mediated by CYP3A and OATP1B. Molecules 2022, 27, 6815. https://doi.org/10.3390/molecules27206815
Garrison DA, Jin Y, Talebi Z, Hu S, Sparreboom A, Baker SD, Eisenmann ED. Itraconazole-Induced Increases in Gilteritinib Exposure Are Mediated by CYP3A and OATP1B. Molecules. 2022; 27(20):6815. https://doi.org/10.3390/molecules27206815
Chicago/Turabian StyleGarrison, Dominique A., Yan Jin, Zahra Talebi, Shuiying Hu, Alex Sparreboom, Sharyn D. Baker, and Eric D. Eisenmann. 2022. "Itraconazole-Induced Increases in Gilteritinib Exposure Are Mediated by CYP3A and OATP1B" Molecules 27, no. 20: 6815. https://doi.org/10.3390/molecules27206815
APA StyleGarrison, D. A., Jin, Y., Talebi, Z., Hu, S., Sparreboom, A., Baker, S. D., & Eisenmann, E. D. (2022). Itraconazole-Induced Increases in Gilteritinib Exposure Are Mediated by CYP3A and OATP1B. Molecules, 27(20), 6815. https://doi.org/10.3390/molecules27206815