Pharmacology: Pharmacodynamics: Paroxetine is a potent and selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor (SSRI). This activity of the drug on brain neurons is thought to be responsible for its antidepressant effects.
Paroxetine is a phenylpiperidine derivative, which is chemically unrelated to the tricyclic or tetracyclic or other available antidepressants. In receptor binding studies, Paroxetine did not exhibit significant affinity for the adrenergic (alpha-1, alpha-2 and beta), dopaminergic, serotonergic (5HT1, 5HT2), or histaminergic receptors of rat brain membrane. This lack of interaction with post-synaptic receptors in vitro is substantiated by in vivo studies which demonstrate lack of CNS depressant and hypotensive properties.
A weak affinity for the muscarinic acetylcholine receptor was evident.
The predominant metabolites of Paroxetine are essentially inactive as 5-HT reuptake inhibitors. These metabolites are polar and conjugated products of oxidation and methylation which are readily cleared.
Pharmacokinetics: Paroxetine is well absorbed after oral administration and undergoes first-pass metabolism. In healthy volunteers, the presence of, or absence of food did not appreciably affect the absorption of a single 30 mg oral dose of Paroxetine. Owing to the extensive distribution of Paroxetine into the tissues, less than 1% of the total drug in the body is believed to reside in the systemic circulation.
Paroxetine is subject to a biphasic process of metabolic elimination which involves presystemic (first-pass) and systemic pathways. First-pass metabolism is extensive, but may be partially saturable, accounting for the increased bioavailability observed with multiple dosing. The metabolism of Paroxetine is accomplished in part by cytochrome P450(2D6). Saturation of the enzyme at clinical doses appears to account for the nonlinearity of Paroxetine kinetics with increasing dose and duration of treatment. The role of this enzyme in Paroxetine metabolism also suggests potential drug-drug interactions (see Precautions). The majority of the dose appears to be oxidised to a catechol intermediate which is converted to highly polar glucuronide and sulphate metabolites through methylation and conjugation reactions. The glucuronide and sulphate conjugates of Paroxetine are about >10,000 and 3,000 times less potent, respectively, than the parent compound as inhibitors of 5-HT reuptake in rat brain synaptosomes. About 64% of an administered dose of Paroxetine is excreted in urine; urinary excretion of unchanged Paroxetine is generally less than 2% of the dose. About 36% of the dose is excreted in the faeces, probably via bile; faecal excretion of unchanged Paroxetine represents less than 1% of the dose. Thus Paroxetine is eliminated almost entirely by metabolism.
A wide range of interindividual variation is observed for the pharmacokinetic parameters. Following the single or multiple dose administration of Paroxetine 20-50 mg, the mean elimination half-life value is about 24 hours, although a range of 3 to 65 hours has been reported. Both the rate of absorption and the terminal elimination half-life appear to be independent of dose.
Steady-state plasma concentrations of Paroxetine are generally achieved in 7 to 14 days, 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).
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 plasma is protein bound at therapeutic concentrations. After the administration of a single 50 mg oral dose to lactating women, the concentrations of the Paroxetine detected in breast milk were similar to those in plasma.