TY - JOUR T1 - Elucidation of the impact of P-glycoprotein and Breast Cancer Resistance Protein on the brain distribution of catechol-O-methyltransferase inhibitors JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.117.077883 SP - dmd.117.077883 AU - Joana Bicker AU - Ana Fortuna AU - Gilberto Alves AU - Patricio Soares-da-Silva AU - Amilcar Falcao Y1 - 2017/01/01 UR - http://dmd.aspetjournals.org/content/early/2017/09/15/dmd.117.077883.abstract N2 - P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are clinically important efflux transporters that act cooperatively at the blood-brain barrier, limiting the entry of several drugs into the CNS and affecting their pharmacokinetics, therapeutic efficacy and safety. In the present study, the interactions of catechol-O-methyltransferase (COMT) inhibitors (BIA 9-1059, BIA 9-1079, entacapone, nebicapone, opicapone and tolcapone) with P-gp and BCRP were investigated in order to determine the contribution of these transporters in their access to the brain. In vitro cellular accumulation and bidirectional transport assays were conducted in MDCK II, MDCK-MDR1 and MDCK-BCRP cells. In vivo pharmacokinetic studies were carried out for tolcapone and BIA 9-1079 in rats, with and without elacridar, a well-known P-gp and BCRP modulator. The results suggest that BIA 9-1079, nebicapone and tolcapone inhibit BCRP in a concentration-dependent manner. Moreover, with net flux ratios higher than 2 and decreased over 50 % in the presence of verapamil or Ko143, BIA 9-1079 was identified as P-gp substrate while BIA 9-1059, entacapone, opicapone and nebicapone revealed to be BCRP substrates. In vivo, brain exposure was limited for tolcapone and BIA 9-1079, although tolcapone crossed the blood-brain barrier in greater rate and extent than BIA 9-1079. The extent of brain distribution of both compounds was significantly increased in the presence of elacridar, attesting the involvement of efflux transporters. These findings provide relevant information and improve the understanding of the mechanisms that govern the access of these COMT inhibitors to the CNS. ER -