Premium
The role of organic anion‐transporting polypeptides and formulation in the clearance and distribution of a novel Na v 1.7 channel blocker
Author(s) -
Pike Andy,
Flanagan Neil J.,
Storer R. Ian,
Swain Nigel A.,
Tseng Elaine
Publication year - 2018
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.2156
Subject(s) - chemistry , distribution (mathematics) , channel blocker , organic cation transport proteins , channel (broadcasting) , pharmacology , transporter , organic chemistry , biochemistry , medicine , mathematics , computer science , mathematical analysis , computer network , gene , calcium
PF‐06456384 is an extremely potent and selective blocker of the Na v 1.7 sodium channel designed as a potential intravenous (i.v.) analgesic targeting high potency and rapid clearance to minimize the potential for residual effects following the end of infusion. In our previous experience targeting oral molecules, the requirement to obtain potent, Na v 1.7 selective molecules led to a focus on acidic, amphipilic compounds cleared primarily by organic anion‐transporting polypeptide mediated hepatic uptake and subsequent biliary excretion. However, the physicochemical properties of the i.v. lead matter were substantially different, moving from acidic, amphiphilic chemical space to zwitterions as well as substantially increasing molecular weight. This report describes the continued relevance of organic anion‐transporting polypeptide driven hepatic uptake in this physicochemical space and highlights an apparent impact of the formulation excipient Solutol on the clearance and distribution of PF‐06456384.