Potent depletion of 5HT from monkey whole blood by a new 5HT uptake inhibitor, paroxetine (FG 7051).

The potent 5-hydroxytryptamine (5HT) uptake inhibitor FG 7051 (paroxetine, INN) was administered to rhesus monkeys in doses of 1.0, 2.5 or 7.5 mg/kg by oral gavage once daily for 13 weeks. Blood samples for analysis of 5HT in whole blood and paroxetine in plasma were taken prior to and after 1, 4 and 13 weeks of treatment. The lowest dose 1 mg/kg caused 30% depletion of 5HT in whole blood with a level of paroxetine in plasma below 2 ng/ml. Doses of 2.5 mg/kg produced an 85% depletion of 5HT and a steady state plasma concentration of about 5 ng paroxetine/ml, while 7.5 mg/kg caused a 93% depletion of 5HT and a steady state plasma concentration of 100--450 ng paroxetine/ml. There was no concentration-dependent 5HT reduction with the highest dose level suggesting that maximal depletion was produced by concentrations below 100 ng/ml. The results showed that paroxetine is a strong depletor of 5HT from whole blood of monkeys conceivably because it inhibits 5HT uptake inhibition. The effect of the drug reached its maximum within 1 week and no tolerance developed during 13 weeks.