Source: Health Products Regulatory Authority (ZA) Revision Year: 2021 Publisher: GlaxoSmithKline South Africa (Pty) Ltd, 39 Hawkins Avenue, Epping Industria 1, 7460
A 1.2 Psycho-analeptics (Antidepressants)
Paroxetine is a selective inhibitor of serotonin (5-hydroxytryptamine, 5-HT) re-uptake and its antidepressant action and efficacy is thought to be related to its specific inhibition of serotonin reuptake in brain neurones.
Paroxetine is chemically unrelated to the tricyclic, tetracyclic and other available antidepressants. The principal metabolites of paroxetine are polar and conjugated products of oxidation and methylation, which are readily cleared. In view of their relative lack of pharmacological activity, it is most unlikely that they contribute to the therapeutic effects of paroxetine.
The metabolites of paroxetine do not compromise its selective action on neuronal 5-HT uptake.
Paroxetine is well absorbed after oral dosing and undergoes first-pass metabolism. AROPAX CR tablets control the dissolution rate of paroxetine over a period of 4 to 5 hours. In addition to controlling the rate of paroxetine release in vivo, an enteric coat delays the start of paroxetine release until AROPAX CR tablets have left the stomach. Compared to immediate release formulations of paroxetine, controlled release tablets have a reduced absorption rate.
Urinary excretion of unchanged paroxetine is generally less than 2% of dose whilst that of metabolites is about 64% of dose. About 36% of the dose is excreted in faeces, probably via the bile, of which unchanged paroxetine represents less than 1% of the dose. Thus paroxetine is eliminated almost entirely by metabolism.
Metabolite excretion is biphasic, being initially a result of first-pass metabolism and subsequently controlled by systemic elimination of paroxetine.
The elimination half-life is variable but is generally about 1 day.
Steady state systemic levels are attained by 7-14 days after starting treatment with immediate or controlled release formulations and pharmacokinetics do not appear to change during long-term therapy. No correlation has been found between paroxetine plasma concentrations and clinical effect (adverse experiences and efficacy).
Due to first-pass metabolism, the amount of paroxetine available to the systemic circulation is less than that absorbed from the gastrointestinal tract. Paroxetine is extensively distributed into tissues and pharmacokinetic calculations indicate that only 1% of the paroxetine in the body resides in the plasma.
Approximately 95% of the paroxetine present in the plasma is protein bound at therapeutic concentrations.
Transfer to human breast milk and to the foetuses of laboratory animals, occurs in small amounts.
Increased plasma concentrations of paroxetine occur in elderly subjects and in those subjects with severe renal and hepatic impairment, but the range of plasma concentrations overlaps that of healthy adult subjects.
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