Pharmacodynamics

SEROQUEL is an antagonist at multiple neurotransmitter receptors in the brain: serotonin 5HT_1A and 5HT₂ (IC_50s=717 & 148nM respectively), dopamine D₁ and D₂ (IC_50s=1268 & 329nM respectively), histamine H₁ (IC₅₀=30nM), and adrenergic α1 and α2 receptors (IC_50s=94 & 271nM, respectively). SEROQUEL has no appreciable affinity at cholinergic muscarinic and benzodiazepine receptors (IC_50s>5000 nM).

The mechanism of action of SEROQUEL, as with other drugs having efficacy in the treatment of schizophrenia and bipolar disorder, is unknown. However, it has been proposed that the efficacy of SEROQUEL in schizophrenia and its mood stabilizing properties in bipolar depression and mania are 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 α1 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.

Distribution: Quetiapine is widely distributed throughout the body with an apparent volume of distribution of 10±4 L/kg. It is 83% bound to plasma proteins at therapeutic concentrations. In vitro, quetiapine did not affect the binding of warfarin or diazepam to human serum albumin. In turn, neither warfarin nor diazepam altered the binding of quetiapine.

Metabolism and Elimination: Following a single oral dose of ¹⁴C-quetiapine, less than 1% of the administered dose was excreted as unchanged drug, indicating that quetiapine is highly metabolized. Approximately 73% and 20% of the dose was recovered in the urine and feces, respectively.

Quetiapine is extensively metabolized by the liver. The major metabolic pathways are sulfoxidation to the sulfoxide metabolite and oxidation to the parent acid metabolite; both metabolites are pharmacologically inactive. In vitro studies using human liver microsomes revealed that the cytochrome P450 3A4 isoenzyme is involved in the metabolism of quetiapine to its major, but inactive, sulfoxide metabolite.

Population Subgroups

Age: Oral clearance of quetiapine was reduced by 40% in elderly patients (≥ 65 years, n=9) compared to young patients (n=12), and dosing adjustment may be necessary (See DOSAGE AND ADMINISTRATION).

Gender: There is no gender effect on the pharmacokinetics of quetiapine.

Race: There is no race effect on the pharmacokinetics of quetiapine.

Smoking: Smoking has no effect on the oral clearance of quetiapine.

Renal Insufficiency: Patients with severe renal impairment (Clcr=10-30 mL/min/1.73 m², n=8) had a 25% lower mean oral clearance than normal subjects (Clcr > 80 mL/min/1.73 m², n=8), but plasma quetiapine concentrations in the subjects with renal insufficiency were within the range of concentrations seen in normal subjects receiving the same dose. Dosage adjustment is therefore not needed in these patients.

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