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Clinical Pharmacokinetics of Selective Serotonin Reuptake Inhibitors

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  • Drug Disposition
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Summary

A feature common to all selective serotonin reuptake inhibitors (SSRIs) is that they are believed to act as antidepressant drugs because of their ability to reversibly block the reuptake of serotonin (5-hydroxytryptamine; 5-HT) in the synaptic cleft. From a chemical perspective, however, they show distinct differences. Consequently, the pharmacokinetic behaviour of the drugs can be very different, and these pharmacokinetic differences may have a major influence on their clinical profiles of action.

All SSRIs have a great affinity for the 5-HT reuptake carrier in the synaptic cleft in the central nervous system, with much less affinity for the noradrenaline (norepinephrine) reuptake carrier, and for α- and β-adrenergic, dopamine, histamine, 5-HT and muscarine receptors. Fluoxetine and citalopram are available as racemic mixtures, the isomers of fluoxetine having almost equal affinity to the 5-HT reuptake carrier, while the reuptake inhibitor properties of citalopram reside almost exclusively in the (+)-isomer. Norfluoxetine, one of the metabolites of fluoxetine, has a selectivity for the 5-HT reuptake carrier comparable with that of fluoxetine.

Gastrointestinal absorption of the SSRIs is generally good, with peak plasma concentrations observed after approximately 4 to 6h. Absolute bioavailability of citalopram is almost 100%, whereas it is likely that the other compounds undergo (substantial) first-pass metabolism. Apparent oral clearance values after single doses range from 26 L/h (citalopram) to 167 L/h (paroxetine), while after multiple doses oral clearance is markedly reduced, particularly for fluoxetine and paroxetine. Plasma protein binding of fluoxetine, paroxetine and sertraline is ⩾95%; values for fluvoxamine (77%) and citalopram (50%) are much lower. For all compounds, however, protein binding interactions do not seem to be of great importance. Although many attempts were made, to date no convincing evidence exists of a relationship between plasma concentrations of any of the SSRIs and clinical efficacy.

Elimination occurs via metabolism, probably in the liver. Renal excretion of the parent compounds is of minor importance. Metabolites of fluvoxamine and fluoxetine are predominantly excreted in urine; larger quantities of metabolites of paroxetine (36%) and sertraline (44%) are excreted in faeces. The half-lives of fluvoxamine, paroxetine, sertraline and citalopram are approximately 1 day. The half-life of fluoxetine is approximately 2 days (6 days after multiple doses), and that of the active metabolite norfluoxetine is 7 to 15 days. The metabolism of paroxetine, and possibly also of fluoxetine, is under genetic control of the sparteine/debrisoquine type.

Available data indicate that metabolism of SSRIs is impaired with reduced liver function. Although renal elimination of SSRIs is minimal, plasma concentrations of paroxetine were increased in patients with renal dysfunction. Metabolism of paroxetine and citalopram, and possibly also sertraline, is impaired in the elderly.

Drug-drug interactions on the level of cytochrome P450 have been described for all SSRIs, but there are profound differences in the isozymes inhibited. Fluvoxamine inhibits the metabolism of propranolol, warfarin, theophylline, bromazepam, carbamazepine, phenazone (antipyrine) and the demethylation of tricyclic antidepressants. Renal excretion of digoxin, atenolol and lithium, and glucuronidation of lorazepam and metabolism of alcohol are not affected: Hydroxylation of tricyclic antidepressants is severely inhibited by fluoxetine, probably because both fluoxetine and norfluoxetine strongly inhibit CYP450IID6. Also the metabolism of carbamazepine and diazepam is impaired, whereas no interaction occurs with lithium, warfarin and alcohol. Phenazone metabolism is not impaired by paroxetine. Digoxin clearance, however, was reduced by 18%, and paroxetine prolonged bleeding time of individuals receiving warfarin. Few drug-drug interaction studies with sertraline and citalopram are reported.

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    Jaap van Harten

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van Harten, J. Clinical Pharmacokinetics of Selective Serotonin Reuptake Inhibitors. Clin. Pharmacokinet. 24, 203–220 (1993). https://doi.org/10.2165/00003088-199324030-00003

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