P-Glycoprotein (MDR1/ABCB1) Restricts Brain Accumulation of the Novel EGFR Inhibitor EAI045 and Oral Elacridar Coadministration Enhances Its Brain Accumulation and Oral Exposure
Abstract
:1. Introduction
2. Results
2.1. In Vitro Transport of EAI045
2.2. Impact of ABCB1 and ABCG2 on Oral EAI045 Plasma and Tissue Distribution over 4 h
2.3. Effect of ABCB1 and ABCG2 on EAI045 Plasma and Tissue Distribution over 30 min
2.4. Effect of ABCB1 and ABCG2 on Plasma and Tissue Distribution of EAI045 Metabolites
2.5. Co-Administration of Elacridar Boosts Brain and Testis Distribution of EAI045
2.6. Impact of OATP1A/1B on Plasma and Tissue Distribution of EAI045 and Its Metabolites
2.7. Assessment of the In Vivo Role of CYP3A in EAI045 Pharmacokinetics
3. Discussion
4. Materials and Methods
4.1. Chemicals
4.2. Transport Assays
4.3. Animals
4.4. Working Solutions
4.5. Plasma and Tissue Pharmacokinetics of EAI045
4.6. LC-MS/MS Analysis
4.7. Pharmacokinetic and Statistical Calculations
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Parameter (EAI045) | Genotype | ||||
---|---|---|---|---|---|
WT | Abcg2-/- | Abcb1a/1b-/- | Abcb1a/1b;Abcg2-/- | WT + Ela | |
Plasma AUC0–30min (h*ng/mL) | 136 ± 80 | 110 ± 41 | 106 ± 57 + | 225 ± 91 | 549 ± 82 ***. +++ |
Fold change AUC | 1.0 | 0.81 | 0.78 | 1.7 | 4.0 |
tmax (min) | 5–30 | 10–30 | 10–30 | 10–30 | 10–30 |
Cmax (ng/mL) | 354 ± 225 | 310 ± 114 | 201 ± 79 | 603 ± 277 | 1512 ± 260 |
Cbrain (ng/g) | 23.3 ± 21.3 | 25.2 ± 17.6 +++ | 82.0 ± 29.7 ++ | 166.9 ± 58.4 *** | 395.9 ± 123.1 ***. +++ |
Fold change Cbrain | 1.0 | 1.1 | 3.5 | 7.2 | 17.0 |
Kp.brain | 0.103 ± 0.059 | 0.094 ± 0.046 +++ | 0.401 ± 0.149 *** | 0.492 ± 0.112 *** | 0.560 ± 0.200 *** |
Fold change Kp.brain | 1.0 | 0.92 | 3.9 | 4.8 | 5.4 |
Ctestis (ng/g) | 22.8 ± 8.9 | 22.8 ± 20.2 ++ | 70.9 ± 36.2 | 80.9 ± 39.4 ** | 198.7 ± 58.9 ***. +++ |
Fold change Ctestis | 1.0 | 1.0 | 3.1 | 3.5 | 8.7 |
Kp.testis | 0.107 ± 0.052 | 0.074 ± 0.015 ++ | 0.329 ± 0.114 *** | 0.231 ± 0.080 ** | 0.280 ± 0.096 ** |
Fold change Kp.testis | 1.0 | 0.69 | 3.1 | 2.2 | 2.6 |
SIWC% | 29.9 ± 11.3 | 29.5 ± 9.1 | 27.6 ± 9.2 | 14.2 ± 8.8 | 4.00 ± 2.57 *** |
Fold change SIWC% | 1.0 | 0.99 | 0.92 | 0.48 (2.1-fold) | 0.13 (7.5-fold) |
Kp.SIWC% | 158 ± 86 | 164 ± 70 + | 148 ± 82 + | 44.4 ± 28.3 * | 5.13 ± 2.63 *** |
Fold change Kp.SIWC% | 1.0 | 1.04 | 0.94 | 0.28 (3.6) | 0.032 (30.8) |
Parameter (Glucuronide) | Genotype | |
---|---|---|
WT | Oatp1a/1b-/- | |
Plasma AUC0–30min (h*ng/mL) | 0.483 ± 0.168 | 7.86 ± 2.91 *** |
Fold change AUC | 1.0 | 16 |
tmax (min) | 5−30 | 5–30 |
Cmax (ng/mL) | 1.53 ± 0.55 | 22.2 ± 8.9 |
Kidney | 17.6 ± 7.3 | 622 ± 475 * |
Fold change kidney | 1.0 | 35 |
Kp.Kidney | 14.8 ± 6.5 | 34.8 ± 11.1 ** |
Fold change Kp.Kidney | 1.0 | 2.4 |
PKidney (*10−6h−1) | 36.0 ± 6.8 | 54.6 ± 14.3 * |
Fold change PKidney | 1.0 | 1.5 |
Liver | 24.7 ± 15.0 | 15.2 ± 9.4 |
Fold change liver | 1.0 | 0.62 |
Kp.Liver | 20.7 ± 13.3 | 0.915 ± 0.315 ** |
Fold change Kp.Liver | 1.0 | 0.044 |
PLiver (*10−6h−1) | 50.3 ± 18.0 | 1.54 ± 0.87 ** |
Fold change PLiver | 1.0 | 0.031 |
SIWC% | 52.3 ± 36.1 | 117 ± 211 |
Fold change SIWC% | 1.0 | 2.2 |
Kp.SIWC% | 46.2 ± 35.7 | 4.08 ± 5.72 ** |
Fold change Kp.SIWC% | 1.0 | 0.088 |
PSIWC% (*10−6h−1) | 102 ± 45 | 5.80 ± 7.84 ** |
Fold change PSIWC% | 1.0 | 0.057 |
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Wang, J.; Susam, M.M.; Gan, C.; Sparidans, R.W.; Lebre, M.C.; Beijnen, J.H.; Schinkel, A.H. P-Glycoprotein (MDR1/ABCB1) Restricts Brain Accumulation of the Novel EGFR Inhibitor EAI045 and Oral Elacridar Coadministration Enhances Its Brain Accumulation and Oral Exposure. Pharmaceuticals 2022, 15, 1124. https://doi.org/10.3390/ph15091124
Wang J, Susam MM, Gan C, Sparidans RW, Lebre MC, Beijnen JH, Schinkel AH. P-Glycoprotein (MDR1/ABCB1) Restricts Brain Accumulation of the Novel EGFR Inhibitor EAI045 and Oral Elacridar Coadministration Enhances Its Brain Accumulation and Oral Exposure. Pharmaceuticals. 2022; 15(9):1124. https://doi.org/10.3390/ph15091124
Chicago/Turabian StyleWang, Jing, M. Merve Susam, Changpei Gan, Rolf W. Sparidans, Maria C. Lebre, Jos H. Beijnen, and Alfred H. Schinkel. 2022. "P-Glycoprotein (MDR1/ABCB1) Restricts Brain Accumulation of the Novel EGFR Inhibitor EAI045 and Oral Elacridar Coadministration Enhances Its Brain Accumulation and Oral Exposure" Pharmaceuticals 15, no. 9: 1124. https://doi.org/10.3390/ph15091124
APA StyleWang, J., Susam, M. M., Gan, C., Sparidans, R. W., Lebre, M. C., Beijnen, J. H., & Schinkel, A. H. (2022). P-Glycoprotein (MDR1/ABCB1) Restricts Brain Accumulation of the Novel EGFR Inhibitor EAI045 and Oral Elacridar Coadministration Enhances Its Brain Accumulation and Oral Exposure. Pharmaceuticals, 15(9), 1124. https://doi.org/10.3390/ph15091124