Refined Tamoxifen Administration in Mice by Encouraging Voluntary Consumption of Palatable Formulations.

Abstract

Drug administration in preclinical rodent models is essential for research and development of novel therapies. Compassionate administration methods have been developed, but these are mostly incompatible with water-insoluble drugs such as tamoxifen or do not allow for precise timing or dosing of the drugs. For more than two decades, tamoxifen has been administered by oral gavage or injection to CreERT2/loxP gene-modified mouse models to spatiotemporally control gene expression, with the numbers of such models steadily increasing in recent years. Animal-friendly procedures for accurately administering tamoxifen or other water-insoluble drugs would therefore have an important impact on animal welfare. Based on a previously published micropipette feeding protocol, we developed palatable formulations to encourage voluntary consumption of tamoxifen. We evaluated the acceptance of the new formulations by mice during training and treatment and assessed the efficacy of tamoxifen-mediated induction of CreERT2/loxP dependent reporter genes. Both sweetened milk and syrup-based formulations encouraged mice to consume tamoxifen voluntarily, but only sweetened milk formulations were statistically non-inferior to oral gavage in inducing CreERT2-mediated gene expression. Serum concentrations of tamoxifen metabolites, quantified using an in-house developed cell assay, confirmed the lower efficacies of syrup- as compared to sweetened milk-based formulations. We found dosing with a micropipette to be more accurate, with the added advantage that the method requires little training for the experimenter. The new palatable solutions encourage voluntary consumption of tamoxifen without loss of efficacy compared to oral gavage and thus represent a refined administration method.