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  • 1
    ISSN: 1432-1041
    Keywords: clozapine ; schizophrenics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The clinical pharmacokinetics of clozapine, an atypical neuroleptic, was evaluated in 10 chronic schizophrenic male patients after intravenous and oral administration. The mean equilibrium-state concentration ratio between blood and plasma was experimentally determined to be 0.87. The average values for blood clearance, hepatic extraction ratio and oral bioavailability were 250 ml/min, 0.2 and 0.27, respectively. Plasma concentration peaked on average at 3 h. The mean volume of distribution at steady-state and the terminal half-life was 1.6 l/kg and 10.3 h, respectively. A large fraction of the dose is most probably metabolized by some extrahepatic presystemic routes. The large inter-individual variability in the bioavailability and clearance is probably the main reason for large variation in the steady-state plasma level in patients receiving the same oral dosage regimen.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-2072
    Keywords: Key words PET ; Pharmacokinetics ; Dopamine D2 receptor ; Serotonin 5HT2 receptor ; Atypical antipsychotic ; Quetiapine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Quetiapine (Seroquel) is a novel antipsychotic with an atypical profile in animal models and a relatively short plasma half-life of 2.5–5 h. In the present study, we used PET to compare the time course of blockade of dopamine D2 and serotonin 5HT2 receptors of quetiapine using C11-raclopride and C11-N-methyl-spiperone as ligands, parallel to monitoring plasma drug concentrations. It was an open study in 11 schizophrenic men using a fixed dose of 450 mg quetiapine. Eight men completed the 29 days treatment, followed by four PET scans performed over a 26-h period after withdrawal of the compound. Quetiapine was shown to bind to dopamine D2 receptors in striatum and 2 h (tmax) after the last dose, 44% receptor occupancy was calculated. After 26 h it had dropped to the same level as was found in untreated healthy volunteers. Serotonin 5HT2 receptor blockade in the frontal cortex was 72% after 2 h, which declined to 50% after 26 h. The terminal plasma half-life of quetiapine was 5.3 h. Clinically, our eight patients had good antipsychotic effect without any extrapyramidal side-effects. Our data shows that quetiapine has a relatively low affinity for dopamine D2 receptors, with an occupancy half-life (10 h), which was about twice as long as that for plasma. A more prolonged blockade of the serotonin 5HT2 receptors was found in the frontal cortex, with receptor occupancy half-life of 27 h. Compared to clozapine, as demonstrated in other studies, quetiapine has much the same ratio of D2/5HT2 occupancy. This could suggest that the combination of D2/5HT2 receptor blockade contributes to the antipsychotic effect and a low incidence of EPS seen with quetiapine in comparative phase three trials. Our results also confirm the clinical data that quetiapine can be administered twice daily.
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