Amitriptyline and fluoxetine are commonly prescribed antidepressants. Loratadine is an antihistamine of the nonsedating class of H1 antagonists. It has recently been reported that amitriptyline, fluoxetine and loratadine stimulate growth of murine tumors (C-3 fibrosarcoma and B16.f10 melanoma). It has further been proposed that these models may provide preclinical screens that compliment current assays of carcinogenic risk that might fail to identify compounds that stimulate tumor growth. This work was undertaken to evaluate the pharmacokinetics, pharmacology, and metabolism in vivo in mice, of the above three commonly prescribed drugs that have been implicated as stimulants of tumor growth. We utilized the same tumor bearing murine model (C57BL) as previous studies and compared the results to published clinical studies to evaluate the model relevance. The pharmacological evaluation of plasma samples obtained from healthy or tumor bearing mice provided estimates of Cp, t½, and the complexity of metabolism. In the first experiment, tumorfree animals were administered a single i.p. dose of test article, and the plasma concentrations of parent and primary metabolite were measured by HPLC during the elimination phase to estimate halflives. Plasma concentrations were constant over 1825 daily doses, and large tumor burdens did not alter the pharmacokinetics. When compared to published results in humans, our results indicate that amitriptyline, fluoxetine and loratadine have significantly different pharmacological characteristics in mice and humans, even at clinically relevant doses The dosing regimen used to assess tumor growth simulation in this model does not produce clinically relevant drug exposures, so extrapolation of murine data to the human would require significant changes in dose scheduling and administration. The proposed murine system is not suitable for modeling tumor proliferation or disease progression in humans to these commonly prescribed antidepressants or antihistamines.