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Assessment and modulation of forsythiaside absorption with MDCKII cells and validation with in situ intestinal experiment

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Abstract

Forsythiaside was characterized by low intestinal absorption by in situ rat experiment and Caco-2 cells. The mechanisms behind this low absorption had not yet been elucidated. The purpose of this study was to investigate the role of efflux transporters in the intestinal absorption of forsythiaside as a potential mechanism for its low small-intestinal absorption following oral administration. Polarized MDCKII cell lines stably transfected with human or murine complementary DNA encoding for various efflux transporters (P-gp/MDR1, MRP2 and Bcrp1) were used to study transepithelial transport of forsythiaside and compare results with the MDCKII-Wild type cells. The transportation inhibitors GF120918, MK571 and Ko143 were used to investigate the transport mechanism. The active transport of forsythiaside was found in MDCKII-WT cells. The MDCKII-MRP2 and MDCKII-Bcrp1 cells significantly increased forsythiaside efflux ratio compared with the parental cells due to the apically directed transport by MRP2 and Bcrp1, respectively. The efflux ratios in MRP2 and Bcrp1 transfected cell lines were greatly decreased in the presence of MK-571 and Ko143, respectively, which indicated that forsythiaside efflux by MRP2 and Bcrp1 were significantly inhibited by their selective inhibitors. MDCKII-MDR1 cells did not exhibit a significant reduction in the forsythiaside efflux compared with the parental cells, indicating that it was not a good substrate for MDR1. And the results were then validated by the in situ experiment. This study presents direct evidence that forsythiaside is effluxed by both MRP2 and Bcrp1, which may contribute to its poor oral bioavailability.

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Acknowledgments

Project supported by the National Natural Science Foundation of China (Grant No. 81102794/H2803), China Postdoctoral Science Foundation (No. 20100471662) and PhD Programs Foundation of Ministry of Education of China (No. 20105132120001).

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Authors and Affiliations

  1. Pharmacy College, Chengdu University of Traditional Chinese Medicine, No. 1166, Liutai Road, Chengdu, 610075, People’s Republic of China

    Yun-Xia Li, Ruo-Qi Zhang & Cheng Peng

  2. The Ministry of Education Key Laboratory of Standardization of Chinese Herbal Medicine, Chengdu, 610075, People’s Republic of China

    Yun-Xia Li, Ruo-Qi Zhang & Cheng Peng

  3. State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu, 610075, People’s Republic of China

    Yun-Xia Li, Ruo-Qi Zhang & Cheng Peng

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  1. Yun-Xia Li
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  2. Ruo-Qi Zhang
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Correspondence to Cheng Peng.

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Li, YX., Zhang, RQ. & Peng, C. Assessment and modulation of forsythiaside absorption with MDCKII cells and validation with in situ intestinal experiment. Eur J Drug Metab Pharmacokinet 37, 179–186 (2012). https://doi.org/10.1007/s13318-012-0088-7

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  • DOI: https://doi.org/10.1007/s13318-012-0088-7

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