J. Lu,1 A. Grangeon,1 F. Gaudette,2 M. Keiser,3 V. Michaud,2 J. Turgeon2; 1Montreal University, Montreal, QC, Canada, 2CRCHUM, Montreal, QC, Canada, 3University Medicine of Greifswald, Greifswald, Germany

BACKGROUND: Triptans are selective agonists of serotonin receptors located on smooth muscle cells of intracranial blood vessels and neurons. Thus, triptans need to cross the blood-brain barrier to reach their site of action. Hydrophilic antimigraine triptans are substrates for OATP1A2, a drug-transporter highly expressed at the human blood-brain barrier. We have previously demonstrated that OATP1A2-mediated transport of the probe drug substrate rosuvastatin was inhibited by compounds composed of a tricyclic ring with a short aliphatic amine chain. The goal of this study was to determine whether naratriptan transport via OATP1A2 can be affected by tricyclic drugs.
METHODS: A HEK293 cell line overexpressing OATP1A2 was used as in vitro model. OATP1A2 cells and control cells were incubated at 37°C for 2 minutes with naratriptan (60µM) and different concentrations of inhibitors (amitriptyline, carazolol, carbamazepine, carbazole, carvedilol, chlorpromazine, clomipramine, desipramine, doxepin, imipramine, nortriptyline, phenothiazine, and trimipramine). Intracellular concentrations of naratriptan were quantified by HPLC-UV.
RESULTS: The transport of naratriptan through OATP1A2 was inhibited by most of the tricyclic compounds evaluated with IC50 values varying between 3.8 to 20.3 µM. Carvedilol had the greatest inhibition potency on naratriptan transport through OATP1A2.
CONCLUSION: Our data suggest that compounds composed of a tricyclic ring with a short aliphatic amine chain, such as carvedilol and tricyclic antidepressants, could modulate the disposition of naratriptan by modulating OATP1A2 transport. The impact of concomitant administration of triptans with potent inhibitors of OATP1A2 on antimigraine efficiency of naratriptan needs to be confirmed.