Inhibition of rat liver tryptophan pyrrolase activity and elevation of brain tryptophan concentration by acute administration of small doses of antidepressants.

1 Administration to rats of a 0.5 mg/kg dose of any of 19 antidepressants, but not that of many other drugs, causes a significant inhibition of the total enzyme and apoenzyme activities of liver tryptophan pyrrolase (of 24-48% and 37-65% respectively) and elevates brain tryptophan concentration by 13-66%. 2 When liver tryptophan pyrrolase activity is enhanced by pretreatment with cortisol or haematin, subsequent administration of a 0.5 mg/kg dose of some, but not other, antidepressants causes inhibition, which is weak (up to 38%). 3 This weak inhibition of the enhanced pyrrolase activity together with other pharmacological and physiological factors could explain the time lag between the start of antidepressant medication and the occurrence of a therapeutic response. 4 The cortisol-induced and haematin-activated pyrrolases respond differentially to inhibition by imipramine and amitriptyline, and this may explain the differential response to these two drugs of depressed patients in relation to urinary excretion of the noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol. 5 The results are discussed in relation to the mechanism of action of antidepressants and the possible involvement of disturbed hepatic tryptophan metabolism in depressive illness.