Relevance of Breast Cancer Resistance Protein to Pharmacokinetics of Florfenicol in Chickens: A Perspective from In Vivo and In Vitro Studies
Abstract
:1. Introduction
2. Results
2.1. Florfenicol is a Substrate of Chicken BCRP Indicated by the Bidirectional Transport Assay in MDCK-chAbcg2 Cells
2.2. Florfenicol Might Favorably Bind with BCRP Analyzed by Molecular Docking Modelling
2.3. Age-Dependent mRNA Expression of BCRP in Kidney and Jejunum in Broilers
2.4. Pharmacokinetic Behavior of Florfenicol Is Different in Broilers at Different Ages
2.5. BCRP Inhibitor Gefitinib Affected the Pharmacokinetics of Florfenicol Orally Administrated in Broilers
3. Discussion
4. Materials and Methods
4.1. Reagents
4.2. Cell Lines
4.3. Animals
4.4. Bidirectional Transport Experiments in MDCK-chAbcg2 Cells
4.5. Molecular Modelling
4.6. BCRP mRNA Expression in Tissues of Broilers at Different Ages by Real Time RT-PCR
4.7. Pharmacokinetic Studies of FFC in Broilers
4.7.1. Experiment Design and Blood Collection
4.7.2. Determination of FFC Concentration in Broilers Serum by HPLC Method
4.7.3. Pharmacokinetic Data Analysis
4.8. Statistical Analysis
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Cell Lines | Inhibitor (Gefitinib) | Papp (×10−6 cm/s) | Efflux Ratio (ER) | p-Values | Net Efflux Ratio (NER) | p-Values | |
---|---|---|---|---|---|---|---|
AP→BL | BL→AP | ||||||
MDCK | − | 0.40 ± 0.04 | 0.40 ± 0.01 | 1.02 ± 0.12 | 0.656 | - | - |
+ | 0.37 ± 0.03 | 0.39 ± 0.01 | 1.06 ± 0.09 | - | |||
MDCK-chAbcg2 | − | 0.28 ± 0.01 | 0.68 ± 0.04 | 2.40 ± 0.08 | 0.000 | 2.37 ± 0.28 | 0.002 |
+ | 0.37 ± 0.02 | 0.43 ± 0.01 | 1.15 ± 0.02 ** | 1.09 ± 0.09 ** |
Molecule | Docking Score (kcal/mol) | Molecule | Docking Score (kcal/mol) |
---|---|---|---|
Substrates | |||
florfenicol | −8.3 | ciprofloxacin | −9.9 |
irinotecan | −12.8 | enrofloxacin | −9.4 |
topotecan | −11.0 | ampicillin | −8.7 |
lapatinib | −11.0 | rosuvastatin | −8.6 |
imatinib | −10.9 | mitoxantrone | −8.3 |
sulfasalazine | −10.7 | clindamycin | −8.0 |
methotrexate | −10.1 | ||
Inhibitors | |||
eltrombopag | −13.0 | elacridar | −12.2 |
gefitinib | −9.6 |
Parameters | 4-Week Old Broilers | 8-Week Old Broilers | p Values | 8-Week Old Broilers Administered Gefitinib | p-Values |
---|---|---|---|---|---|
Cmax (μg/mL) | 3.87 ± 0.96 | 2.93 ± 1.07 | 0.159 | 1.73 ± 0.48 | 0.079 |
Tmax (h) | 0.63 ± 0.21 | 0.62 ± 0.19 | 0.943 | 2.00 ± 1.41 | 0.064 |
T1/2β (h) | 3.27 ± 1.20 | 0.94 ± 0.17 * | 0.012 | 3.50 ± 3.35 | 0.224 |
Vd (L/kg) | 3.42 ± 1.18 | 5.64 ± 0.60 ** | 0.005 | 7.39 ± 2.98 | 0.327 |
ClB (L/h/kg) | 2.43 ± 0.53 | 4.43 ± 1.46 * | 0.034 | 2.57 ± 0.52 # | 0.048 |
AUC0~12h (mg·h/L) | 8.58 ± 1.88 | 4.91 ± 1.56 ** | 0.007 | 8.01 ± 1.65 # | 0.023 |
F (%) | 79.30 | 48.04 | - | 78.38 | - |
Parameters | 4-Week Old Broilers | 8-Week Old Broilers | p-Values |
---|---|---|---|
T1/2β (h) | 1.0 ± 0.85 | 0.79 ± 0.18 | 0.598 |
Vd (L/kg) | 1.51 ± 0.62 | 1.18 ± 0.29 | 0.310 |
ClB (L/h/kg) | 1.65 ± 0.54 | 2.14 ± 0.67 | 0.239 |
AUC0~12h (mg·h/L) | 5.41 ± 0.31 | 5.11 ± 1.89 | 0.741 |
Gene | Forward (5′–3′) | Reverse (5′–3′) | Length/bp | Tm (°C) |
---|---|---|---|---|
β-actin | ATGTGGATCAGCA AGCAGGAGTA | TTTATGCGCATTT ATGGGTTTTGT | 300 | 54.1 |
Abcg2 | CCTACTTCCTGGCC TTGATGT | TCGGCCTGCTATA GCTTGAAATC | 180 | 56 |
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Liu, Y.; Guo, L.; Zloh, M.; Zhang, Y.; Huang, J.; Wang, L. Relevance of Breast Cancer Resistance Protein to Pharmacokinetics of Florfenicol in Chickens: A Perspective from In Vivo and In Vitro Studies. Int. J. Mol. Sci. 2018, 19, 3165. https://doi.org/10.3390/ijms19103165
Liu Y, Guo L, Zloh M, Zhang Y, Huang J, Wang L. Relevance of Breast Cancer Resistance Protein to Pharmacokinetics of Florfenicol in Chickens: A Perspective from In Vivo and In Vitro Studies. International Journal of Molecular Sciences. 2018; 19(10):3165. https://doi.org/10.3390/ijms19103165
Chicago/Turabian StyleLiu, Yang, Li Guo, Mire Zloh, Yujuan Zhang, Jinhu Huang, and Liping Wang. 2018. "Relevance of Breast Cancer Resistance Protein to Pharmacokinetics of Florfenicol in Chickens: A Perspective from In Vivo and In Vitro Studies" International Journal of Molecular Sciences 19, no. 10: 3165. https://doi.org/10.3390/ijms19103165