The contribution of pre-clinical drug evaluation in predicting the clinical profile of the selective serotonin reuptake inhibitor paroxetine

Selective serotonin reuptake inhibitors (SSRIs) such as paroxetine have been produced as an alternative to the less selective antidepressants such as the tricyclic antidepressants (TCAs) and the monamine oxidase inhibitors (MAOIs). The potency and selectivity of paroxetine as an SSRI was determined firstly in vitro using synaptosomes and subsequently in ex vivo animal studies. The pharmacokinetic profile of paroxetine in animals suggested that it is well absorbed following oral administration, is highly plasma protein bound and almost completely hepatically biotransformed to pharmacologically inactive metabolites which are renally eliminated. Toxicity studies indicate that paroxetine has a wide therapeutic index when compared to TCAs. Clinical signs emanating from these studies were mainly related to the gastrointestinal tract and CNS. No cardiovascular alterations were observed in animals. Mild anticholinergic properties have been demonstrated both in vitro and in vivo. The activity of paroxetine as an antidepressant has been confirmed in some animal models of depression but not surprisingly is inactive in such tests that are based on the noradrenergic system. These preclinical studies suggested that paroxetine was an antidepressant with an improved safety profile over previously discovered antidepressants. Clinically, this has been confirmed with fewer adverse effects, similar efficacy and no deaths to date being reported following overdosage with paroxetine. Drug-drug interactions mag occur due to inhibition of the hepatic isoenzyme CYP4502D6, exacerbation of the serotonin syndrome and due to displacement by potent plasma protein bound drugs. These studies clearly demonstrate the utility of the preclinical profile of paroxetine in predicting its position as an antidepressant.