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Irinotecan Alters the Disposition of Morphine Via Inhibition of Organic Cation Transporter 1 (OCT1) and 2 (OCT2)

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Abstract

Purpose

The organic cation transporters (OCTs) and multidrug and toxin extrusions (MATEs) together are regarded as an organic cation transport system critical to the disposition and response of many organic cationic drugs. Patient response to the analgesic morphine, a characterized substrate for human OCT1, is highly variable. This study was aimed to examine whether there is any organic cation transporter-mediated drug and drug interaction (DDI) between morphine and commonly co-administrated drugs.

Methods

The uptake of morphine and its inhibition by six drugs which are commonly co-administered with morphine in the clinic were assessed in human embryonic kidney 293 (HEK293) cells stably expressing OCT1, OCT2 and MATE1. The in vivo interaction between morphine and the select irinotecan was determined by comparing the disposition of morphine in the absence versus presence of irinotecan treatment in mice.

Results

The uptake of morphine in the stable HEK293 cells expressing human OCT1 and OCT2 was significantly increased by 3.56 and 3.04 fold, respectively, than that in the control cells, with no significant uptake increase in the cells expressing human MATE1. All of the six drugs examined, including amitriptyline, fluoxetine, imipramine, irinotecan, ondansetron, and verapamil, were inhibitors of OCT1/2-mediated morphine uptake. The select irinotecan significantly increased the plasma concentrations and decreased hepatic and renal accumulation of morphine in mice.

Conclusions

Morphine is a substrate of OCT1 and OCT2. Clinician should be aware that the disposition of and thus the response to morphine may be altered by co-administration of an OCT1/2 inhibitor, such as irinotecan.

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Acknowledgments and Disclosures

The present study was partially supported by the National Natural Science Foundation (NNSF) of China (81,570,533, Q.L.) and the Natural Science Foundation for Young Scientist of Hunan Province, China (2018JJ3829, Q.L.). Dr. Yan Shu received funding supports from the National Institute of General Medical Sciences of the National Institutes of Health (NIH) under Award R01GM099742 (Y.S.) and the US Food and Drug Administration (FDA) under Award U01FD004320 (J.E.P, Y.S.). Dr. Dong Guo is an M-CERSI Scholar (FDA 1U01FD005946). Dr. Yan Shu is a co-founder for and owns equity in Optivia Biotechnology. Designed Research: Yan Shu, Qing Li, Wei Zhang, James E. polli, Honghao Zhou. Performed Research: Peng Zhu, Zhi Ye, Zongping Xiong, Shiqiong Huang, Dong Guo. Analyzed Data: Peng Zhu, Zhi Ye, Qing Li, Dong Guo, Jun Guo. Wrote Manuscript: Peng Zhu, Qing Li, Yan Shu. All authors approved the version to be submitted.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 110 Xiangya Road, Changsha, 410078, Hunan, China

    Peng Zhu, Zongping Xiong, Shiqiong Huang, Jun Guo, Wei Zhang, Honghao Zhou, Qing Li & Yan Shu

  2. Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, 20 Penn Street, HSFII Room 555, Baltimore, Maryland, 21201, USA

    Zhi Ye, Dong Guo, James E. Polli, Qing Li & Yan Shu

  3. Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, 410078, China

    Zhi Ye

  4. Key Laboratory of Oral Medicine, School and Hospital of Stomatology, Guangzhou Medical University, Guangzhou, 510140, China

    Dong Guo & Yan Shu

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  1. Peng Zhu
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  7. Wei Zhang
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  10. Qing Li
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  11. Yan Shu
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Correspondence to Qing Li or Yan Shu.

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Zhu, P., Ye, Z., Guo, D. et al. Irinotecan Alters the Disposition of Morphine Via Inhibition of Organic Cation Transporter 1 (OCT1) and 2 (OCT2). Pharm Res 35, 243 (2018). https://doi.org/10.1007/s11095-018-2526-y

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  • DOI: https://doi.org/10.1007/s11095-018-2526-y

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