EFFECTS OF ACUTE PAROXETINE ADMINISTRATION ON TRYPTOPHAN-METABOLISM AND DISPOSITION IN THE RAT

1 The effects of acute oral administration of paroxetine on tryptophan metabolism and disposition were examined in the rat. 2 Basal liver tryptophan pyrrolase activity was inhibited by paroxetine in vitro and after oral administration. Maximum inhibition was caused by a 1 mg kg-1 dose. 3 Paroxetine administration also inhibited pyrrolase activity that had previously been enhanced by hormonal induction by cortisol or cofactor activation by haematin. The cortisol induction of the enzyme was, however, not inhibited by pretreatment of rats with paroxetine. 4 Paroxetine increased tryptophan availability to the brain, because of the above pyrrolase-inhibitory mechanism. Cerebral 5-hydroxytrytamine (5-HT) synthesis was accordingly enhanced, though this was apparent only with doses of the drug of up to 1 mg kg-1. With larger doses, decreased 5-HT turnover, probably as a result of 5-HT uptake inhibition, was the more dominant feature. 5 Paroxetine lowered circulating corticosterone concentration, but did not influence those of albumin, non-esterified fatty acids or glucose. 6 It is concluded that, in addition to inhibiting brain 5-HT turnover, paroxetine also, in common with 20 other antidepressants, enhances 5-HT synthesis by increasing brain tryptophan concentration secondarily to inhibition of liver tryptophan pyrrolase activity.