Breast Cancer Resistance Protein and Multidrug Resistance Protein 2 Regulate the Disposition of Acacetin Glucuronides
| Autor: | Haihui Zheng, Ming Hu, Ying Wang, Xiaoxiao Qi, Jiamei Chen, Jinjun Wu, Zhongqiu Liu, Xinchun Wang, Jia Yu, Lijun Zhu, Huangyu Jiang |
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| Rok vydání: | 2016 |
| Předmět: |
Male
ATP Binding Cassette Transporter Subfamily B Abcg2 Glucuronidation Pharmaceutical Science Biological Availability Pharmacology 030226 pharmacology & pharmacy 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Glucuronides Pharmacokinetics Tandem Mass Spectrometry ATP Binding Cassette Transporter Subfamily G Member 2 Animals Humans Pharmacology (medical) Tissue Distribution Intestinal Mucosa biology Acacetin Multidrug resistance-associated protein 2 Organic Chemistry Flavones Bioavailability chemistry Liver 030220 oncology & carcinogenesis Area Under Curve biology.protein Molecular Medicine Female Efflux Caco-2 Cells Glucuronide Biotechnology Half-Life |
| Zdroj: | Pharmaceutical research. 34(7) |
| ISSN: | 1573-904X |
| Popis: | To determine the mechanism responsible for acacetin glucuronide transport and the bioavailability of acacetin. Area under the curve (AUC), clearance (CL), half-life (T1/2) and other pharmacokinetic parameters were determined by the pharmacokinetic model. The excretion of acacetin glucuronides was evaluated by the mouse intestinal perfusion model and the Caco-2 cell model. In pharmacokinetic studies, the bioavailability of acacetin in FVB mice was 1.3%. Acacetin was mostly exposed as acacetin glucuronides in plasma. AUC of acacetin-7-glucuronide (Aca-7-Glu) was 2-fold and 6-fold higher in Bcrp1 (−/−) mice and Mrp2 (−/−) mice, respectively. AUC of acacetin-5-glucuronide (Aca-5-Glu) was 2-fold higher in Bcrp1 (−/−) mice. In mouse intestinal perfusion, the excretion of Aca-7-Glu was decreased by 1-fold and 2-fold in Bcrp1 (−/−) and Mrp2 (−/−) mice, respectively. In Caco-2 cells, the efflux rates of Aca-7-Glu and Aca-5-Glu were significantly decreased by breast cancer resistance protein (BCRP) inhibitor Ko143 and multidrug resistance protein 2 (MRP2) inhibitor LTC4. The use of these inhibitors markedly increased the intracellular acacetin glucuronide content. BCRP and MRP2 regulated the in vivo disposition of acacetin glucuronides. The coupling of glucuronidation and efflux transport was probably the primary reason for the low bioavailability of acacetin. |
| Databáze: | OpenAIRE |
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