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Quantitative assessment of TRPM5‐dependent oral aversiveness of pharmaceuticals using a mouse brief access taste aversion (BATA) assay.
Author(s) -
Palmer Roy Kyle,
Devantier Heather,
Long Daniel James,
Carlucci Stacy Anne,
Hendrix Cynthia Joy,
Bryant Robert
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a420
Subject(s) - taste , pharmacology , bitter taste , medicine , chemistry , food science
Many orally administered pharmaceuticals are regarded by humans as aversive, most often described as “bitter.” Taste aversiveness often leads to patient noncompliance and reduced treatment effectiveness. “Bitter” taste is mediated by T2R GPCRs through a peripheral signaling pathway critically dependent upon function of the TRPM5 ion channel. The BATA assay operationally defines aversive taste as suppression of the rate at which a rodent licks from sipper tubes that deliver tastant solutions or suspensions. We have used a mouse BATA assay for rapid quantification of oral aversiveness from a set of 20 pharmaceutical active ingredients (APIs). Robust lick‐rate dose‐response functions were obtained from both C57BL/6J (WT) and C57BL6/TRPM5 −/− (TRPM5 KO) mouse strains, generating reliable determinations of potency and relative maximal oral aversiveness for each API. A subset of APIs also was evaluated in a human bitterness assessment test; EC50s from both the human test and WT mouse BATA were equivalent. Relative to WT potencies, EC50s from TRPM5 KO mice were right‐shifted >10‐fold for all but four APIs. Cetirizine, dextromethorphan, sumatriptan, and valproate EC50s were essentially identical in both mouse strains, indicating a TRPM5‐independent alternative aversive pathway. Our results suggest the BATA assay will facilitate formulation strategies and taste assessment of late development‐phase APIs.