Jennifer Lu, Alexia Grangeon, Fleur Gaudette, Jacques Turgeon and Veronique Michaud
OATP1A2 is a membrane drug-transporter expressed at the human blood-brain barrier (BBB) that may potentially mediate penetration of drugs in the brain. Triptans, hydrophilic antimigraine drugs, are substrates of OATP1A2. It is believed that triptans should cross the BBB to reach their site of action. Thus, OATP1A2 can limit brain penetration of triptans and may consequently influence their antimigraine drug action. We have previously demonstrated that compounds composed of a tricyclic ring with a short aliphatic amine chain, such as tricyclic antidepressants and carvedilol, inhibited OATP1A2-mediated rosuvastatin uptake. The main objective of this study was to determine whether triptans transport via OATP1A2 is affected by tricyclic compounds. First, we confirmed that triptans were substrates of OATP1A2 but not OATP2B1 using HEK293 stable cell lines. The tricyclic drugs evaluated were able to inhibit OATP1A2-mediated uptake of triptans. carvedilol was the most potent inhibitor. Potential inhibition was assessed with a range of total plasma concentrations of the drugs. Carvedilol and nortriptyline lowered the uptake of both almotriptan and zolmitriptan whereas clomipramine diminished the uptake of almotriptan only. Our data suggest that these three drugs may limit the penetration of triptans to the brain by modulating OATP1A2 transport at clinically relevant concentrations.