Role of P-glycoprotein and permeability upon the brain distribution and pharmacodynamics of etamicastat: a comparison with nepicastat.
1. This study explores the impact of permeability and P-glycoprotein (P-gp) efflux, upon brain exposure to etamicastat, a new dopamine-β-hydroxylase (DBH) inhibitor and consequently brain levels of catecholamines. 2. Brain exposure to etamicastat (10 mg/kg), following intravenous administration to mice, was residual and upon oral administration of the same dose no compound was detected, concurring with the absence of effects upon brain catecholamines. The intravenous co-administration of elacridar (1.0 mg/kg), a known P-gp/BCRP dual modulator, significantly increased brain etamicastat exposure, but the levels attained were very low when compared to those of nepicastat, a centrally active DBH inhibitor. 3. In vitro permeability studies from apical-to-basal direction conducted in Caco-2 cells and MDCK-II cells showed that etamicastat apparent permeability was 1.2 × 10(-5) and 1.1 × 10(-6 )cm/s, respectively, 5- and 50-fold lower as compared to nepicastat. The secretory efflux ratio in MDCK-II cells overexpressing human P-gp showed an efflux ratio greater than 2, for both compounds, which was significantly decreased by elacridar. Despite its lower bioavailability and higher clearance, as compared to nepicastat, etamicastat showed preferential distribution to peripheral tissues and high plasma free fraction (15.5%), which may explain its effects upon peripheral DBH and catecholamine levels. 4. Though P-gp-mediated efflux may contribute to the limited brain penetration of etamicastat, the low permeability along with the pharmacokinetic properties of etamicastat may be perceived as the main contributors for its peripheral selectivity, which is advantageous for a cardiovascular drug candidate.
a Department of Research and Development , Mamede do Coronado , Portugal .
Ana I
AI
Loureiro
Maria João
MJ
Bonifácio
Carlos
C
Fernandes-Lopes
Nuno
N
Pires
Bruno
B
Igreja
Lyndon C
LC
Wright
Patrício
P
Soares-da-Silva
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000166:Acridines / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001262:Atenolol / Q000494:pharmacology; D001578:Benzopyrans / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D001798:Blood Proteins / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D018938:Caco-2 Cells; D002395:Catecholamines / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects*; D004285:Dogs; D004299:Dopamine beta-Hydroxylase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D051379:Mice; D011433:Propranolol / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000494:pharmacology; D013871:Thiones / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D014018:Tissue Distribution / Q000187:drug effects
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D001578:Benzopyrans; D001798:Blood Proteins; D002395:Catecholamines; D007093:Imidazoles; D044005:Tetrahydroisoquinolines; D013871:Thiones; D001262:Atenolol; C509002:etamicastat; D011433:Propranolol; D004299:Dopamine beta-Hydroxylase; C083501:Elacridar; C109487:nepicastat
Blood–brain barrier; P-glycoprotein; dopamine; dopamine-β-hydroxylase; etamicastat; noradrenaline; sympathetic nervous system