Source: Health Products Regulatory Authority (ZA) Revision Year: 2023 Publisher: AstraZeneca Pharmaceuticals (Pty) Limited, Building 2 Northdowns Office Park, 17 Georgian Crescent West, Bryanston, Johannesburg, 2191, South Africa
A 2.6.5 Central nervous system depressants: Miscellaneous structures
Quetiapine is an atypical antipsychotic agent, which interacts with a broad range of neurotransmitter receptors. Quetiapine exhibits a higher affinity for serotonin (5HT2) receptors in the brain than it does for dopamine D1 and D2 receptors in the brain. Quetiapine has no affinity for the norepinephrine transporter (NET) and low affinity for the serotonin 5HT1A receptor, whereas norquetiapine has high affinity for both. Inhibition of NET and partial agonist action at 5HT1A sites by norquetiapine may contribute to TRUVALIN’s therapeutic efficacy as an antidepressant. Quetiapine and norquetiapine have high affinity at histaminergic and adrenergic alpha1 receptors and moderate affinity at adrenergic alpha2 receptors. Quetiapine also has low or no affinity for muscarinic receptors, while norquetiapine has moderate to high affinity for several muscarinic receptor subtypes, which may explain anti-cholinergic (muscarinic) effects.
In animal models, quetiapine is active in tests for antipsychotic activity, such as conditioned avoidance
Quetiapine does not produce sustained elevations in prolactin in man.
Quetiapine, when given twice a day, maintains 5HT2 and D2 receptor occupancy for up to 12 hours after dosing.
Quetiapine is absorbed and extensively metabolised following oral administration. The principal human plasma metabolites do not have significant pharmacological activity. The bioavailability of quetiapine is not significantly affected by administration with food. The elimination half-life of quetiapine is approximately 7 hours. Quetiapine is approximately 65% - 83% bound to plasma proteins.
The pharmacokinetics of quetiapine are variable but do not differ significantly between men and women.
The mean clearance of quetiapine in the elderly is approximately 30-50% lower than that seen in adults aged 18-65 years.
The mean plasma clearance of quetiapine was reduced by approximately 25% in subjects with severe renal impairment (creatinine clearance less than 30 ml/min/1,73m²) and in subjects with hepatic impairment (stable alcoholic cirrhosis), but the individual clearance values are within the range for normal subjects.
Quetiapine is extensively metabolised with the parent compound accounting for less than 5% of unchanged medicine-related material in the urine or faeces, following the administration of radio-labelled quetiapine. Approximately 73% of the radioactivity is excreted in the urine and 21% in the faeces.
In vitro investigations established that CYP3A4 is the primary enzyme responsible for cytochrome P450 mediated metabolism of quetiapine.
Quetiapine and several of its metabolites were found to be weak inhibitors of human cytochrome P450 1A2, 2C9, 2C19, 2D6 and 3A4 activities, but only at concentrations at least 10-50 fold higher than those observed
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