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Research ArticleSpecial Section on Natural Products: Experimental Approaches to Elucidate Disposition Mechanisms and Predict Pharmacokinetic Drug Interactions

Organic Cation Transporter 1 and 3 Contribute to the High Accumulation of Dehydrocorydaline in the Heart

Yingchun Chen, Cui Li, Yaodong Yi, Weijuan Du, Huidi Jiang, Su Zeng and Hui Zhou
Drug Metabolism and Disposition October 2020, 48 (10) 1074-1083; DOI: https://doi.org/10.1124/dmd.120.000025
Yingchun Chen
Laboratory of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
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Cui Li
Laboratory of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
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Yaodong Yi
Laboratory of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
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Weijuan Du
Laboratory of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
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Huidi Jiang
Laboratory of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
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Su Zeng
Laboratory of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
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Hui Zhou
Laboratory of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
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Abstract

Dehydrocorydaline (DHC), one of the main active components of Corydalis yanhusuo, is an important remedy for the treatment of coronary heart disease. Our previous study revealed a higher unbound concentration of DHC in the heart than plasma of mice after oral administration of C. yanhusuo extract or DHC, but the underlying uptake mechanism remains unelucidated. In our investigations, we studied the transport mechanism of DHC in transgenic cells, primary neonatal rat cardiomyocytes, and animal experiments. Using quantitative real-time polymerase chain reaction and Western blotting, we found that uptake transporters expressed in the mouse heart include organic cation transporter 1/3 (OCT1/3) and carnitine/organic cation transporter 1/2 (OCTN1/2). The accumulation experiments in transfected cells showed that DHC was a substrate of OCT1 and OCT3, with Km of 11.29 ± 3.3 and 8.96 ± 3.7 μM, respectively, but not a substrate of OCTN1/2. Additionally, a higher efflux level (1.71-fold of MDCK-mock) of DHC was observed in MDCK-MDR1 cells than in MDCK-mock cells. Therefore, DHC is a weak substrate for MDR1. Studies using primary neonatal rat cardiomyocytes showed that OCT1/3 inhibitors (quinidine, decynium-22, and levo-tetrahydropalmatine) prevented the accumulation of DHC, whereas OCTN2 inhibitors (mildronate and l-carnitine) did not affect its accumulation. Moreover, the coadministration of OCT1/3 inhibitors (levo-tetrahydropalmatine, THP) decreased the concentration of DHC in the mouse heart. Based on these findings, DHC may be accumulated partly by OCT1/3 transporters and excreted by MDR1 in the heart. THP could alter the distribution of DHC in the mouse heart.

Significance Statement We reported the cardiac transport mechanism of dehydrocorydaline, highly distributed to the heart after oral administration of Corydalis yanhusuo extract or dehydrocorydaline only. Dehydrocorydaline (an OCT1/3 and MDR1 substrate) accumulation in primary cardiomyocytes may be related to the transport activity of OCT1/3. This ability, hampered by selective inhibitors (levo-tetrahydropalmatine, an inhibitor of OCT1/3), causes a nearly 40% reduction in exposure of the heart to dehydrocorydaline. These results suggest that OCT1/3 may contribute to the uptake of dehydrocorydaline in the heart.

Footnotes

    • Received March 20, 2020.
    • Accepted July 16, 2020.
  • This work was supported by the Zhejiang Provincial Natural Science Foundation of China [Grant LY19H310005] and the National Natural Science Foundation of China [Grant 81673504, 81872929].

  • All authors declare that there are no conflicts of interest.

  • https://doi.org/10.1124/dmd.120.000025.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 48 (10)
Drug Metabolism and Disposition
Vol. 48, Issue 10
1 Oct 2020
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Research ArticleSpecial Section on Natural Products: Experimental Approaches to Elucidate Disposition Mechanisms and Predict Pharmacokinetic Drug Interactions

The High Accumulation of Dehydrocorydaline in Heart

Yingchun Chen, Cui Li, Yaodong Yi, Weijuan Du, Huidi Jiang, Su Zeng and Hui Zhou
Drug Metabolism and Disposition October 1, 2020, 48 (10) 1074-1083; DOI: https://doi.org/10.1124/dmd.120.000025

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Research ArticleSpecial Section on Natural Products: Experimental Approaches to Elucidate Disposition Mechanisms and Predict Pharmacokinetic Drug Interactions

The High Accumulation of Dehydrocorydaline in Heart

Yingchun Chen, Cui Li, Yaodong Yi, Weijuan Du, Huidi Jiang, Su Zeng and Hui Zhou
Drug Metabolism and Disposition October 1, 2020, 48 (10) 1074-1083; DOI: https://doi.org/10.1124/dmd.120.000025
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