Seroquel

[Quetiapine]

Clinical Pharmacology
CLINICAL PHARMACOLOGY

Pharmacodynamics

SEROQUEL is an antagonist at multiple neurotransmitter receptors in the brain: serotonin 5HT1A and 5HT2 (IC50s= 717 & 148nM respectively), dopamine D1 and D2 (IC50s= 1268 & 329nM respectively), histamine H1 (IC50= 30nM), and adrenergic a1 and a2 receptors (IC50s= 94 & 271nM, respectively). SEROQUEL has no appreciable affinity at cholinergic muscarinic and benzodiazepine receptors (IC50s> 5000 nM).

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The mechanism of action of SEROQUEL, as with other antipsychotic drugs, is unknown. However, it has been proposed that this drug's therapeutic activity in schizophrenia is mediated through a combination of dopamine type 2 (D2) and serotonin type 2 (5HT2) antagonism. Antagonism at receptors other than dopamine and 5HT2 with similar receptor affinities may explain some of the other effects of SEROQUEL. SEROQUEL's antagonism of histamine H1 receptors may explain the somnolence observed with this drug.

SEROQUEL's antagonism of adrenergic a1 receptors may explain the orthostatic hypotension observed with this drug.

Pharmacokinetics

Quetiapine fumarate activity is primarily due to the parent drug. The multiple-dose pharmacokinetics of quetiapine are dose-proportional within the proposed clinical dose range, and quetiapine accumulation is predictable upon multiple dosing.

Elimination of quetiapine is mainly via hepatic metabolism with a mean terminal half-life of about 6 hours within the proposed clinical dose range. Steady-state concentrations are expected to be achieved within two days of dosing. Quetiapine is unlikely to interfere with the metabolism of drugs metabolized by cytochrome P450 enzymes.

Absorption

Quetiapine fumarate is rapidly absorbed after oral administration, reaching peak plasma concentrations in 1.5 hours. The tablet formulation is 100% bioavailable relative to solution. The bioavailability of quetiapine is marginally affected by administration with food, with Cmax and AUC values increased by 25% and 15%, respectively.

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