藥物轉運蛋白、代謝?與藥物之生可用率息息相關。前人研究顯示，許多多酚化合物會影響藥物運輸蛋白及代謝?的功能或表現，因此當富含多酚的保健食品與藥物併用時，可能改變藥物生可用率，甚至影響療效或毒性。基於臨床用藥安全考量，本研究以藥物動力學方法，利用大鼠為模型，探討多酚保健食品包括桑椹、蔓越莓、諾麗果對ABC 運輸蛋白(ATP-binding cassette transporters) 與代謝?cytochrome P450 enzymes (CYPs) 受質藥物動力學之影響。本研究的探針藥物包括cyclosporine (CSP)、gefitinib 及methotrexate (MTX)。藥物在血中及細胞中之濃度利用螢光偏極免疫法或LC-MS/MS 進行分析，並以各種體外模型進行機制探討。
結果顯示，桑椹顯著降低CSP 的生可用率，機轉研究顯示，桑椹提升了P-glycoprotein (P-gp) 及CYP 3A4 之活性；蔓越莓顯著增加gefitinib 的生可用率，機轉研究顯示，蔓越莓抑制了breast cancer resistance protein (BCRP)、CYP 3A4 及CYP 2D6 之活性；諾麗果顯著增加MTX 的生可用率，並延長其平均滯留時間，機轉研究顯示，諾麗果抑制了multidrug resistance-associated protein 2
(MRP 2) 及BCRP 之活性。
本研究提出多酚保健食品對ABC 運輸蛋白及代謝?調控之實證資訊，可供臨床醫療人員及民眾參考，應有助提高民眾之用藥安全。
Drug transporters and metabolizing enzymes are associated with drug bioavailability. Recent studies have reported that many polyphenols affected the function and expression of drug transporters and metabolizing enzymes. Therefore, coadministration of dietary supplements with substrates of drug transporters or metabolizing enzymes may alter the pharmacokinetics and pharmacodynamics, even resulted in toxicity of critical medicines. Based on the consideration of drug safety, this study investigated the effects of dietary supplements including mulberry, cranberry and noni juice on the pharmacokinetics of substrates of ATP-binding cassette (ABC) transporters and cytochrome P450 enzymes (CYPs) in rats. Cyclosporine (CSP), gefitinib and methotrexate (MTX) were used as probe drugs in this study and their concentrations in blood and cells were measured by specific monoclonal fluorescence polarization immunoassay and LC-MS/MS method. Furthermore, in vitro models were used for mechanism study.
Our results showed that mulberry significantly decreased the bioavailability of CSP through activating P-glycoprotein (P-gp) and CYP 3A4. Cranberry significantly increased the bioavailability of gefitinib through inhibiting the activities of breast cancer resistance protein (BCRP), CYP 3A4 and CYP 2D6. Noni significantly increased the bioavailability and mean residence time of MTX through inhibiting the activities of BCRP and multidrug resistance-associated protein 2 (MRP 2).
In conclusion, this study provided the evidences that dietary supplements modulated ABC transporters and CYPs, which would be valuable for the clinical professionals and general public to enhance drug safety.
