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MDR1 and OAT1/OAT3 Mediate the Drug-Drug Interaction between Puerarin and Methotrexate

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Abstract

Purpose

To conduct in vivo and in vitro experiments to investigate puerarin (PUR), an isoflavone C-glyoside, and elucidate its ability to alter methotrexate (MTX) transport and pharmacokinetics.

Methods

In vivo absorption studies, in vitro everted intestinal sac preparation, kidney slices in rats and bi-directional transport assay with mock-/MDCK-MDR1 cells, uptake studies in HEK293-OAT1/3 cells were employed to evaluate the interaction.

Results

In vivo and in vitro MTX absorption in rats were enhanced in combination with PUR. PUR inhibited digoxin efflux transport in MDCK-MDR1 monolayers with an IC50 value of 1.6 ± 0.3 μM, suggesting that the first target of drug interaction was MDR1 in the intestine during the absorption process. MTX renal clearance decreased significantly after simultaneous intravenous administration. MTX uptake in rat kidney slices and HEK293-OAT1/3 cells were markedly inhibited by PUR, suggesting that the second target of drug interaction was OATs located in the kidney. Moreover, concomitant administration of PUR reduced renal MTX accumulation and plasma levels of creatinine and BUN.

Conclusions

Co-administration of PUR enhanced MTX exposure by inhibition of intestinal MDR1 and renal OAT1/3. Although the renal damage of MTX was improved by PUR, the high level exposure of MTX should be cautious in the clinical usage.

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Abbreviations

AUC:

Area under the plasma concentration-time curve

BUN:

Blood urea nitrogen

CLP :

Plasma clearance

CLR :

Renal clearance

CsA:

Cyclosporin A

DDI:

Drug-drug interaction

KRB:

Krebs-Ringer buffer

MDR:

Multidrug resistance

MDR1:

Multidrug resistance 1

MTX:

Methotrexate

OAT:

Organic anion transporter

PAH:

p-amino hippuric acid

PCG:

Penicillin G

PUR:

Puerarin

VER:

Verapamil hydrochloride

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Acknowledgments and Disclosures

This work was supported by a grant from the National Natural Science Foundation of China (No. 81273580, 81072694) and the Dalian Government (No. 2010E12SF060). We wish to express our deep gratitude to Professor Zeng Su (College of Pharmacy, Zhejiang University, China) for providing MDCK-MDR1 cells and Professors Yuichi Sugiyama (Graduate School of Pharmaceutical Sciences, University of Tokyo) and Gong Likun (Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai, China) for providing HEK293-OAT1/3 cells.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road Lvshunkou District, Dalian, 116044, China

    Qi Liu, Changyuan Wang, Qiang Meng, Xiaokui Huo, Huijun Sun, Jinyong Peng, Xiaochi Ma, Pengyuan Sun & Kexin Liu

  2. Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian, China

    Qi Liu, Changyuan Wang, Qiang Meng, Xiaokui Huo, Huijun Sun, Jinyong Peng, Xiaochi Ma, Pengyuan Sun & Kexin Liu

  3. Research Institute of Integrated Traditional and Western Medicine Dalian Medical University, Dalian, China

    Kexin Liu

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Liu, Q., Wang, C., Meng, Q. et al. MDR1 and OAT1/OAT3 Mediate the Drug-Drug Interaction between Puerarin and Methotrexate. Pharm Res 31, 1120–1132 (2014). https://doi.org/10.1007/s11095-013-1235-9

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  • DOI: https://doi.org/10.1007/s11095-013-1235-9

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