Quetiapine
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Mechanism of action
The mechanism of action of quetiapine in the listed indications is unclear. However, the efficacy of quetiapine in
these indications could be mediated through a combination of dopamine type 2 (D
2) and serotonin type 2 (5HT
2)
antagonism. The active metabolite, N-desalkyl quetiapine (norquetiapine), has similar activity at D
2, but greater
activity at 5HT
2Areceptors, than the parent drug (quetiapine).
.
Pharmacodynamics
Quetiapine and its metabolite, norquetiapine, have affinity for multiple neurotransmitter receptors with norquetiapine
binding with higher affinity than quetiapine in general. The Ki values for quetiapine and norquetiapine at the dopamine
D
1are 428/99.8 nM, at D
2626/489nM, at serotonin 5HT
1A1040/191 nM at 5HT
2A38/2.9 nM, at histamine H
14.4/1.1
nM, at muscarinic M
11086/38.3 nM, and at adrenergic α
1b 14.6/46.4 nM and, at α
2receptors 617/1290 nM, respectively. Quetiapine and norquetiapine lack appreciable affinity to the benzodiazepine receptors.
Effect
on
QT
Interval
In clinical trials quetiapine was not associated with a persistent increase in QT intervals. However, the QT effect was not systematically evaluated in a thorough QT study. In post marketing experience there were cases reported of QT prolongation in patients who overdosed on quetiapine [see
OVERDOSAGE(
10.1
)], in patients with concomitant illness, and in patients taking medicines known to cause electrolyte imbalance or increase QT interval.
Pharmacokinetics
Absorption
Adults
Quetiapine 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.
Children
and
Adolescents
At steady state the pharmacokinetics of the parent compound, in children and adolescents (10 to 17 years of age), were similar to adults. However, when adjusted for dose and weight, AUC and C
maxof the parent compound were 41% and 39% lower, respectively, in children and adolescents than in adults. For the active metabolite, norquetiapine, AUC and C
maxwere 45% and 31% higher, respectively, in children and adolescents than in adults. When adjusted for dose and weight, the pharmacokinetics of the metabolite, norquetiapine, was similar between children and adolescents and adults [see
USE
IN
SPECIFIC
POPULATIONS(
8.4
)].
Absorption
Quetiapine 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 C
maxand 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 and in the metabolism of its active metabolite N-desalkyl quetiapine.
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(
2.3
)].
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 (Cl
cr=10 to 30 mL/min/1.73 m
2, n=8) had a 25% lower mean oral clearance than normal subjects (Cl
cr>80 mL/min/1.73 m
2, 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 [see
USE
IN
SPECIFIC
POPULATIONS(
8.6
)].
Hepatic Insufficiency
Hepatically impaired patients (n=8) had a 30% lower mean oral clearance of quetiapine than normal subjects. In two of the 8 hepatically impaired patients, AUC and C
maxwere 3 times higher than those observed typically in healthy subjects. Since quetiapine is extensively metabolized by the liver, higher plasma levels are expected in the hepatically impaired population, and dosage adjustment may be needed [see
DOSAGE
AND …
External links
Source: DailyMed — Quetiapine ↗
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