Tomoxetine (LY139603) selectively inhibits norepinephrine uptake in animals and has activity in animal models of depression. Tomoxetine was administered in single oral doses up to 90 mg to healthy normal volunteers. In addition, normal human subjects received either 20 or 40 mg of tomoxetine b.i.d. for 1 week to evaluate the safety and pharmacologic activity of the compound in humans. At these doses, no serious drug-related adverse effects were encountered. Activity of the compound at the lower dose (20 mg b.i.d.) was evaluated by examining changes in the pressor responses to infused norepinephrine and tyramine and by determining [3H]serotonin uptake in platelets harvested from subjects receiving the compound. Pressor sensitivity to norepinephrine was increased by 261 +/- 69% of control, and pressor sensitivity to tyramine was decreased by 51 +/- 6% of control during treatment. Changes in the pressor sensitivity to norepinephrine in individual subjects were positively correlated with drug levels. There were no statistically significant changes in platelet [3H]serotonin uptake. These results indicate that tomoxetine selectively inhibits norepinephrine uptake in humans at doses which are clinically well tolerated and suggest that tomoxetine has potential clinical use as an antidepressant.
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