Peng Zhu1, Zhi Ye2,3, Dong Guo2,4, Zongping Xiong1, Shiqiong Huang1, Jun Guo1, Wei Zhang1, James E Polli2, Honghao Zhou1, Qing Li5,6, Yan Shu7,8,9. 1. Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 110 Xiangya Road, Changsha, 410078, Hunan, China. 2. Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, 20 Penn Street, HSFII Room 555, Baltimore, Maryland, 21201, USA. 3. Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, 410078, China. 4. Key Laboratory of Oral Medicine, School and Hospital of Stomatology, Guangzhou Medical University, Guangzhou, 510140, China. 5. Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 110 Xiangya Road, Changsha, 410078, Hunan, China. liqing9251026@csu.edu.cn. 6. Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, 20 Penn Street, HSFII Room 555, Baltimore, Maryland, 21201, USA. liqing9251026@csu.edu.cn. 7. Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 110 Xiangya Road, Changsha, 410078, Hunan, China. yshu@rx.umaryland.edu. 8. Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, 20 Penn Street, HSFII Room 555, Baltimore, Maryland, 21201, USA. yshu@rx.umaryland.edu. 9. Key Laboratory of Oral Medicine, School and Hospital of Stomatology, Guangzhou Medical University, Guangzhou, 510140, China. yshu@rx.umaryland.edu.
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.
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 humanOCT1, 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 humanembryonic kidney293 (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 humanOCT1 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 humanMATE1. 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.
Entities:
Keywords:
drug and drug interactions; irinotecan; morphine; organic cation transporters
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