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Irinotecan Alters the Disposition of Morphine Via Inhibition of Organic Cation Transporter 1 (OCT1) and 2 (OCT2).
- Source :
-
Pharmaceutical research [Pharm Res] 2018 Oct 25; Vol. 35 (12), pp. 243. Date of Electronic Publication: 2018 Oct 25. - Publication Year :
- 2018
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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.<br />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.<br />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.<br />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.
- Subjects :
- Amitriptyline metabolism
Amitriptyline pharmacology
Animals
Drug Interactions
Fluoxetine metabolism
Fluoxetine pharmacology
HEK293 Cells
Humans
Imipramine metabolism
Imipramine pharmacology
Irinotecan pharmacology
Mice, Inbred C57BL
Ondansetron metabolism
Ondansetron pharmacology
Organic Cation Transport Proteins metabolism
Organic Cation Transporter 1 metabolism
Organic Cation Transporter 2 metabolism
Tissue Distribution
Verapamil metabolism
Verapamil pharmacology
Irinotecan metabolism
Morphine metabolism
Narcotics metabolism
Organic Cation Transporter 1 antagonists & inhibitors
Organic Cation Transporter 2 antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1573-904X
- Volume :
- 35
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Pharmaceutical research
- Publication Type :
- Academic Journal
- Accession number :
- 30361780
- Full Text :
- https://doi.org/10.1007/s11095-018-2526-y