Quantitative assessment of TRPM5-dependent oral aversiveness of pharmaceuticals using a mouse brief-access taste aversion assay

Abstract

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 G-protein coupled receptors through a peripheral signaling pathway critically dependent upon function of the TRPM5 ion channel. The brief-access taste aversion (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 active pharmaceutical ingredients (APIs). Robust lick-rate dose-response functions were obtained from both C57BL/6J wild type (WT) and C57BL/6J/TRPM5-/- (TRPM5 knockout) mouse strains, generating reliable determinations of potency and relative maximal oral aversiveness for each API. A subset of APIs was also evaluated in a human bitterness assessment test; effective concentrations for half-maximum responses (EC50s) from both the human test and WT mouse BATA were equivalent. Relative to WT potencies, EC50s from TRPM5 knockout mice were right-shifted more than 10-fold for most APIs. However, APIs were identified for which 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.

Development of a model for robust and exploratory analysis of the rodent brief-access taste aversion data

“…Data from BATA experiments are generally displayed by concentration-response curves representing the means of the number of licks or "lick ratios" as a function of the concentrations of the compound tested and the standard error (SE) or standard deviation (SD) obtained with a number n of rats (3,5,7,8,11,12,(15)(16)(17)(18). This way of presenting the results can…”

“…Among these approaches, the rodent BATA model has a great potential and has already shown very promising results comparable to human panel data (3,4). The BATA model has been widely used and documented in the literature for different purposes (3)(4)(5)(6)(7)(8)(9). In this animal model, rodents such as mice or rats, are mildly water-deprived and then put into a "lickometer" which records the number of "licks" that the rodents make to different concentrations of the compound under test samples presented in several sipper tubes.…”

Bitter tastant responses in the amoeba Dictyostelium correlate with rat and human taste assays

“…Since taste responses are based in the peripheral gustatory system along with a central nervous system recognition component, most research in this area employs animals or human-based tests. Currently, one technique employed to assess the palatability of drugs, including novel chemical entities (NCE), is the brief access taste aversion (BATA) model using the rat (Rudnitskaya et al, 2013) or mouse (Devantier et al, 2008). Although this assay is not considered harmful to the animals and has demonstrable translation to humans for identification of bitter tastants (Rudnitskaya et al, 2013), it is potentially unpleasant for the animal (due to the aversive nature of some of the substances tested), is relatively expensive, time consuming and has a limited throughput capacity.…”

“…BATA tests were performed between 09.00 and 13.00. The BATA assay (see Devantier et al, 2008;Clapham et al, 2012 for additional details) employed an automated apparatus (MS-160 Davis Rig gustatory behavior apparatus, DiLog Instruments, Tallahassee, FL, USA) to measure the number of licks in response to water, a calibration compound or the test compound. The percentage inhibition at various concentrations of the test substance presented on multiple occasions in random order was used to calculate the IC 50 (curve fitting with a four parameter logistic curve restrained to zero; SAS) for test substances with 12 rats used per group to test each substance.…”

Pharmacologic Antagonism of the Oral Aversive Taste-Directed Response to Capsaicin in a Mouse Brief Access Taste Aversion Assay

“…With an array of ligands available as pharmacologic tools, the TRPV1 taste response potentially could be pharmacologically characterized in both animals and humans. Here, we describe the use of TRPV1 agonists and antagonists in a pharmacologic evaluation of taste-directed licking in a brief access taste aversion (BATA) assay (Devantier et al, 2008).…”