title: Common drugs inhibit human organic cation transporter 1 (OCT1)-mediated neurotransmitter uptake.
abstract: The human organic cation transporter 1 (OCT1) is a polyspecific transporter involved in the uptake of positively charged and neutral small molecules in the liver. To date, few endogenous compounds have been identified as OCT1 substrates; more importantly, the effect of drugs on endogenous substrate transport has not been examined. In this study, we established monoamine neurotransmitters as substrates for OCT1, specifically characterizing serotonin transport in human embryonic kidney 293 cells. Kinetic analysis yielded a Km of 197 micomolar and a Vmax of 561 pmol/mg protein/minute for serotonin. Furthermore, we demonstrated that serotonin uptake was inhibited by diphenhydramine, fluoxetine, imatinib, and verapamil, with IC50 values in the low micromolar range. These results were recapitulated in primary human hepatocytes, suggesting that OCT1 plays a significant role in hepatic elimination of serotonin and that xenobiotics may alter the elimination of endogenous compounds as a result of interactions at the transporter level.
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center (K.H.B., B.H., J.N.L.), The University of Kansas Cancer Center (B.H.), and The University of Kansas Liver Center (B.H., J.N.L.), Kansas City, Kansas.
authors.forename: Kelli H
authors.initials: KH
authors.lastname: Boxberger
authors.forename: Bruno
authors.initials: B
authors.lastname: Hagenbuch
authors.forename: Jed N
authors.initials: JN
authors.lastname: Lampe
mesh_terms: D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism; D057809:HEK293 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D018377:Neurotransmitter Agents / Q000378:metabolism; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000378:metabolism; D027702:Organic Cation Transporter 1 / Q000037:antagonists & inhibitors* / Q000502:physiology*; D004364:Pharmaceutical Preparations / Q000008:administration & dosage*; D012701:Serotonin / Q000378:metabolism*
chemical_list: D018377:Neurotransmitter Agents; D027702:Organic Cation Transporter 1; D004364:Pharmaceutical Preparations; D012701:Serotonin; D004298:Dopamine; D009638:Norepinephrine