Mechanism of Action

The mechanism of action of quetiapine, as with other drugs having efficacy in the treatment of schizophrenia, is unknown. However, it is believed that this drug's efficacy in schizophrenia is mediated through a combination of dopamine type 2 (D₂) and serotonin type 2 (5HT₂) antagonism, by quetiapine and its active metabolite N-desalkyl quetiapine.

Antagonism at receptors other than dopamine D₂ and serotonin 5HT₂ with similar or greater affinities may explain some of the other effects of quetiapine and N-desalkyl quetiapine; antagonism at histamine H₁ receptors may explain the somnolence and antagonism at adrenergic α1 receptors may explain the orthostatic hypotension observed with this drug.

Pharmacodynamics

Quetiapine is an antagonist at multiple neurotransmitter receptors in the brain: serotonin 5HT1_A 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). Quetiapine has no appreciable affinity at cholinergic muscarinic and benzodiazepine receptors (IC_50s > 5000 nM).

Pharmacokinetics

Following multiple dosing of quetiapine up to a total daily dose of 800 mg, administered in divided doses, the plasma concentration of quetiapine and N-desalkyl quetiapine, the major active metabolite of quetiapine, were proportional to the total daily dose. Accumulation is predictable upon multiple dosing. Steady-state mean Cmax and AUC of N-desalkyl quetiapine are about 21-27% and 46-56%, respectively of that observed for quetiapine. Elimination of quetiapine is mainly via hepatic metabolism. The mean-terminal half-life is approximately 7 hours for quetiapine and 9 to 12 hours for N- desalkyl quetiapine within the clinical dose range. Steady- state concentrations are expected to be achieved within two days of dosing. SEROQUEL XR is unlikely to interfere with the metabolism of drugs metabolized by cytochrome P450 enzymes.

Absorption

Quetiapine fumarate reaches peak plasma concentrations approximately 6 hours following administration. SEROQUEL XR dosed once daily at steady-state has comparable bioavailability to an equivalent total daily dose of SEROQUEL administered in divided doses, twice daily. A high-fat meal (approximately 800 to 1000 calories) was found to produce statistically significant increases in the SEROQUEL XR Cmax and AUC of 44% to 52% and 20% to 22%, respectively, for the 50-mg and 300-mg tablets. In comparison, a light meal (approximately 300 calories) had no significant effect on the Cmax or AUC of quetiapine. It is recommended that SEROQUEL XR be taken without food or with a light meal [see DOSAGE AND ADMINISTRATION].

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. The average dose fraction of free quetiapine and its major active metabolite is < 5% excreted in the urine.

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