Quetiapine: Difference between revisions
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| pk_absorption = Quetiapine is rapidly absorbed after oral administration; peak plasma concentrations of the immediate-release tablet occur approximately 1.5 hours after dosing. The tablet formulation is essentially completely bioavailable (~100%) relative to oral solution, but the parent compound is extensively metabolized on first pass through the liver, and the doses required for clinical effect are correspondingly larger than what reaches the systemic circulation in unchanged form. The extended-release formulation produces a slower, more sustained absorption profile with peak levels at approximately 6 hours and substantially flatter plasma trajectories. High-fat meals increase the Cmax of the extended-release formulation by approximately 50% and the AUC by approximately 20%, leading to the labeled recommendation that Seroquel XR be taken without food or after a light meal.<ref name="seroquel-label">U.S. Food and Drug Administration. Seroquel (quetiapine) prescribing information. NDA 020639.</ref> | | pk_absorption = Quetiapine is rapidly absorbed after oral administration; peak plasma concentrations of the immediate-release tablet occur approximately 1.5 hours after dosing. The tablet formulation is essentially completely bioavailable (~100%) relative to oral solution, but the parent compound is extensively metabolized on first pass through the liver, and the doses required for clinical effect are correspondingly larger than what reaches the systemic circulation in unchanged form. The extended-release formulation produces a slower, more sustained absorption profile with peak levels at approximately 6 hours and substantially flatter plasma trajectories. High-fat meals increase the Cmax of the extended-release formulation by approximately 50% and the AUC by approximately 20%, leading to the labeled recommendation that Seroquel XR be taken without food or after a light meal.<ref name="seroquel-label">U.S. Food and Drug Administration. Seroquel (quetiapine) prescribing information. NDA 020639.</ref> | ||
| pk_distribution = Plasma protein binding is approximately 83%, primarily to [[Albumin|albumin]] and [[Alpha-1-acid glycoprotein|alpha-1-acid glycoprotein]]. Volume of distribution approximately 10 L/kg. Quetiapine crosses the [[Blood-brain barrier|blood-brain barrier]] readily and the placenta in modest amounts; it is excreted into breast milk at low concentrations.<ref name="seroquel-label"/> | | pk_distribution = Plasma protein binding is approximately 83%, primarily to [[Albumin|albumin]] and [[Alpha-1-acid glycoprotein|alpha-1-acid glycoprotein]]. Volume of distribution approximately 10 L/kg. Quetiapine crosses the [[Blood-brain barrier|blood-brain barrier]] readily and the placenta in modest amounts; it is excreted into breast milk at low concentrations.<ref name="seroquel-label"/> | ||
| pk_metabolism = Quetiapine is extensively metabolized in the liver, predominantly via [[ | | pk_metabolism = Quetiapine is extensively metabolized in the liver, predominantly via [[Enzyme:CYP3A4|CYP3A4]], with minor contributions from [[Enzyme:CYP2D6|CYP2D6]]. The principal active metabolite is N-desalkylquetiapine (also called norquetiapine), formed via CYP3A4-mediated dealkylation; norquetiapine has a longer half-life (~9-12 hours) than the parent compound (~6 hours) and a distinct receptor binding profile, with substantially higher affinity for the [[Norepinephrine transporter|norepinephrine transporter]] (NET) than the parent compound. The norquetiapine NET binding is one mechanism proposed for quetiapine's efficacy in bipolar depression and as an MDD adjunct, distinguishing it pharmacodynamically from neuroleptics whose active metabolites are less behaviorally distinctive. Several other inactive metabolites are formed in lesser amounts. Quetiapine itself has negligible CYP-inhibitory activity but is sensitive to inhibition and induction of CYP3A4.<ref name="seroquel-label"/> | ||
| pk_elimination = Elimination is renal (73%) and fecal (20%), almost entirely as metabolites; less than 1% of an oral dose is recovered unchanged in urine. Mean parent half-life is approximately 6 hours for immediate-release quetiapine; the active norquetiapine metabolite has a half-life of approximately 9-12 hours and contributes meaningfully to the clinical duration of action. Half-life is prolonged in elderly patients (mean clearance reduced approximately 30-50%) and in hepatic impairment.<ref name="seroquel-label"/> | | pk_elimination = Elimination is renal (73%) and fecal (20%), almost entirely as metabolites; less than 1% of an oral dose is recovered unchanged in urine. Mean parent half-life is approximately 6 hours for immediate-release quetiapine; the active norquetiapine metabolite has a half-life of approximately 9-12 hours and contributes meaningfully to the clinical duration of action. Half-life is prolonged in elderly patients (mean clearance reduced approximately 30-50%) and in hepatic impairment.<ref name="seroquel-label"/> | ||
| pharmacodynamics = Quetiapine is a broad-receptor-binding atypical neuroleptic with the receptor profile that defines the second-generation class: substantial antagonism at both serotonin [[5-HT2A receptor|5-HT2A]] and dopamine [[Dopamine receptor D2|D2]] receptors, with the 5-HT2A:D2 affinity ratio higher than at the older neuroleptics. The conventional explanation for the lower extrapyramidal liability of atypical neuroleptics is that pre-frontal 5-HT2A antagonism increases mesocortical [[Dopamine|dopamine]] release while striatal D2 occupancy is partial, reducing the basal-ganglia dopamine blockade that drives the movement-disorder spectrum. | | pharmacodynamics = Quetiapine is a broad-receptor-binding atypical neuroleptic with the receptor profile that defines the second-generation class: substantial antagonism at both serotonin [[5-HT2A receptor|5-HT2A]] and dopamine [[Dopamine receptor D2|D2]] receptors, with the 5-HT2A:D2 affinity ratio higher than at the older neuroleptics. The conventional explanation for the lower extrapyramidal liability of atypical neuroleptics is that pre-frontal 5-HT2A antagonism increases mesocortical [[Dopamine|dopamine]] release while striatal D2 occupancy is partial, reducing the basal-ganglia dopamine blockade that drives the movement-disorder spectrum. | ||