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Sertraline is primarily a serotonin reuptake inhibitor (SRI).
Therapeutic doses of sertraline (50-200 mg/day) taken by patients
for four weeks resulted in 80-90% inhibition of serotonin transporter
(SERT) in striatum as measured by positron emission tomography.
9 mg/day was sufficient to inhibit 50% of SERT. Sertraline is also
a dopamine reuptake inhibitor with 1% of its SRI potency and sigma-1
receptor agonist with 5% of its SRI potency. Sertraline weakly blocks
a1-adrenoreceptors with 1-10% of its SRI potency.
Pharmacokinetics
Taken orally, sertraline is absorbed slowly, achieving its maximal
concentration in the plasma 4-6 hours after ingestion. 98.5% of
sertraline in the blood is bound to the plasma proteins. Its half-life
in the body is 13-45 hours and is about 1.5 times longer in women
(32 hours) than in men (22 hours), resulting in the proportionally
1.5 higher exposure of women. According to in vitro studies, sertraline
is metabolized by several cytochrome 450 isoforms: CYP2D6, CYP2C9,
CYP2B6, CYP2C19 and CYP3A4, and it appeared unlikely that inhibition
of any single isoform could cause clinically significant changes
of the sertraline pharmacokinetics. No differences in sertraline
pharmacokinetics were observed between people with high and low
activity of CYP2D6; however, poor CYP2C19 metabolizers had a 1.5
higher level of sertraline than the normal metabolizers. In vitro
data also indicate that the inhibition of CYP2B6 should have even
greater effect than the inhibition of CYP2C19, while the contribution
CYP2C9 and CYP3A4 to the sertraline metabolism would be minor. These
conclusions, though, have not been verified in human studies. Sertraline
can be deaminated in vitro by monoamine oxidases; however, this
metabolic pathway has never been studied in vivo. The major metabolite
of sertraline, desmethylsertraline, is about 50-time weaker serotonin
transporter inhibitor than sertraline and its clinical effect is
negligible. |
