Cranberry Ingestion Modulated Drug Transporters and Metabolizing Enzymes: Gefitinib Used as a Probe Substrate in Rats
Abstract
:1. Introduction
2. Results
2.1. Quantitation of Gefitinib and O-Desmethyl Gefitinib in Serum
2.2. Effect of CJ Intake on Gefitinib Pharmacokinetics in Rats
2.3. Effect of CJ on P-gp Activity
2.4. Effect of CM on CYP2D6 Activity
2.5. Effect of CJ Ingestion on the Protein Levels of P-gp, BCRP, CYP3A4 and CYP2D6
3. Discussion
4. Materials and Methods
4.1. Chemicals and Reagents
4.2. Characterization of Polyphenols in CJ
4.3. Animals, Drug Administration and Blood Collection
4.4. Quantitation of Gefitinib and O-Desmethyl Gefitinib in Serum and Method Validation
4.5. Cell Line and Culture Conditions
4.6. Cell Viability Assay
4.7. Effect of CJ on P-gp Activity
4.8. Preparation of CM
4.9. Effect of CM on CYP2D6 Activity
4.10. Western Blot Analysis of P-gp, BCRP, CYP3A4 and CYP2D6 in Rat Enterocytes and Hepatocytes
4.11. Data Analysis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Conflicts of Interest
Sample Availability
Abbreviations
ACN | acetonitrile |
AUC | the area under the serum concentration-time curve |
BCRP | breast cancer resistance protein |
CJ | cranberry juice |
CYP | cytochrome P450 |
Cmax | peak blood concentration |
CM | serum metabolites of cranberry |
DMEM | Dulbecco’s modified Eagle medium |
DMSO | dimethyl sulfoxide |
ECL | chemiluminescence |
FBS | fetal bovine serum |
HBSS | Hank’s buffered salt solution |
HPLC | high-performance liquid chromatography |
MDCKII | Madin-Darby canine kidney type II cells |
MRT | mean residence time |
MTT | 3-(4′,5′-dimethylthiazol-2′-yl)-2,5-diphenyltetrazolium bromide |
NEAA | nonessential amino acid |
P-gp | P-glycoprotein |
PSG | penicillin streptomycin and glutamine |
R123 | rhodamine 123 |
SDS | sodium dodecyl sulfate |
TBST | Tris-buffered saline with 0.1% Tween® 20 detergent |
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Treatments | Gefitinib + Water | Gefitinib + CJ | |
---|---|---|---|
Parameters | |||
Tmax (min) | 264.0 ± 44.9 | 216.0 ± 44.9 | |
Cmax (μg/mL) | 1.8 ± 0.3 a | 2.3 ± 0.2 b | |
(+28%) | |||
AUC0-t (μg⋅min/mL) | 1170.5 ± 129.3 a | 1818.2 ± 144.8 b | |
(+55%) | |||
MRT (min) | 511.3 ± 40.1 | 543.0 ± 29.8 |
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Yu, C.-P.; Tsai, P.-L.; Li, P.-Y.; Hsu, P.-W.; Lin, S.-P.; Lee Chao, P.-D.; Hou, Y.-C. Cranberry Ingestion Modulated Drug Transporters and Metabolizing Enzymes: Gefitinib Used as a Probe Substrate in Rats. Molecules 2022, 27, 5772. https://doi.org/10.3390/molecules27185772
Yu C-P, Tsai P-L, Li P-Y, Hsu P-W, Lin S-P, Lee Chao P-D, Hou Y-C. Cranberry Ingestion Modulated Drug Transporters and Metabolizing Enzymes: Gefitinib Used as a Probe Substrate in Rats. Molecules. 2022; 27(18):5772. https://doi.org/10.3390/molecules27185772
Chicago/Turabian StyleYu, Chung-Ping, Pei-Ling Tsai, Pei-Ying Li, Pei-Wen Hsu, Shiuan-Pey Lin, Pei-Dawn Lee Chao, and Yu-Chi Hou. 2022. "Cranberry Ingestion Modulated Drug Transporters and Metabolizing Enzymes: Gefitinib Used as a Probe Substrate in Rats" Molecules 27, no. 18: 5772. https://doi.org/10.3390/molecules27185772