Impact of quercetin on pharmacokinetics of quetiapine: insights from in-vivo studies in wistar rats.

Quercetin (QCN) is commonly used in high doses as a dietary supplement for weight loss. Psychotic patients are at greater risk of developing obesity than the general population. The present study was designed to understand the impact of QCN on the exposure of quetiapine (QTE), an anti-psychotic drug with narrow therapeutic index and brain penetrating capability. The content of QTE in rat plasma was analyzed through liquid chromatography-tandem mass spectrometry. The results showed a significant (p < 0.05) increase in exposure of QTE (peroral dosed) in the animals pre-treated with QCN as compared to the control group. All the animals pre-treated with QCN, succumbed to death within 3-5 min of intravenous dosing of QTE (1 mg/kg). The studies in rat liver S9 fraction indicated that QCN could increase the metabolic stability of QTE by inhibiting the activity of CYP enzymes. The brain to plasma ratio of QTE increased upon QCN pre-treatment (2.6 vs 7.7), which could be attributed to P-glycoprotein inhibition at the blood-brain barrier by QCN. The current set of studies indicated that serious herb-drug interaction between QCN and QTE might occur when they are co-administered. Caution is advised for concomitant use of QCN rich dietary supplements with QTE.

A Positron Emission Tomography Study of Norepinephrine Transporter Occupancy and Its Correlation with Symptom Response in Depressed Patients Treated with Quetiapine XR.

Background: Quetiapine is effective in treating depressive symptoms in major depressive disorder and bipolar disorder, but the mechanisms underlying its antidepressants effects are unknown. Norquetiapine, a metabolite of quetiapine, has high affinity for norepinephrine transporter, which might account for its therapeutic efficacy. Methods: In this study, we used positron emission tomography with (S,S)-[11C]O-methyl reboxetine to estimate norepinephrine transporter density and assess the relationship between norepinephrine transporter occupancy by quetiapine XR and improvement in depression in patients with major depressive disorder (n=5) and bipolar disorder (n=5). After the baseline positron emission tomography scan, patients were treated with quetiapine XR with a target dose of 150 mg in major depressive disorder and 300 mg in bipolar disorder. Patients had a second positron emission tomography scan at the end of week 2 and a final scan at week 7. Results: Norepinephrine transporter density was significantly lower in locus ceruleus in patients compared with healthy subjects. Further, there was a significant positive correlation between quetiapine XR dose and norepinephrine transporter occupancy in locus ceruleus at week 2. The norepinephrine transporter occupancy at week 2 in hypothalamus but not in other regions predicted improvement in depression as reflected by reduction in MADRS scores from baseline to week 7. The estimated dose of quetiapine XR associated with 50% norepinephrine transporter occupancy in hypothalamus at week 2 was 256 mg and the estimated plasma levels of norquetiapine to achieve 50% norepinephrine transporter occupancy was 36.8 µg/L. Conclusion: These data provide preliminary support for the hypothesis that norepinephrine transporter occupancy by norquetiapine may be a contributor to the antidepressant effects of quetiapine.

Effect of a dosing-time on quetiapine-induced acute hyperglycemia in mice.

Although rare, second-generation antipsychotic drugs cause severe hyperglycemia within several days after the initiation of therapy. Because glucose tolerance exhibits circadian rhythmicity, we evaluated an effect of a dosing-time on quetiapine-induced acute hyperglycemia in mice. A single intraperitoneal dose of quetiapine dosing-time-independently induced insulin resistance in fasted C57BL/6J mice. However, acute hyperglycemic effect was detected only after dosing of the drug at the beginning of an active phase. Under the conditions in which hepatic glucose production was stimulated by pyruvate administration, hyperglycemic effect of quetiapine was dosing-time-independently observed. In addition, the dosing-time-dependent hyperglycemic effect of quetiapine disappeared in the liver-specific circadian clock-disrupted mice in which circadian rhythmicity in hepatic glucose production is deranged. Furthermore, the dosing-time had little impact on the pharmacokinetics of quetiapine in normal mice. These results suggest that quetiapine acutely causes hyperglycemia only when hepatic glucose production elevates. Therefore, quetiapine therapy with once daily dosing at a rest phase might be safer than that at an active phase. Further studies are needed to confirm the hypothesis.

Pre-clinical investigation of the modulation of quetiapine plasma pharmacokinetics and tissues biodistribution by lipid-core nanocapsules.

This study aims to investigate the changes in plasma pharmacokinetics and liver and brain distribution of quetiapine (QTP) due to its encapsulation into a polymeric nanocarrier. For this reason a bioanalytical method was developed and validated in order to quantify QTP in plasma, liver and brain tissue samples. The method was linear over the concentration range of 0.025-3.0µg.mL (r(2)>0.98), accurate, precise (R.S.D<±15%) and the recoveries, stability and validation parameters are within the acceptable limits determined by international guidelines. Plasma pharmacokinetics, cerebral and hepatic distribution of the drug were carried out after intravenous administration of 5mgkg(-1) of nanoencapsulated (QLNC) or free-QTP to male Wistar rats. Increasing half-life was observed for QLNC in relation to free-QTP due to o significant decrease in total clearance. QTP volume of distribution was not altered due to encapsulation. An increase in QTP liver exposure was observed after nanoencapsulation probably due to a reduction in drug metabolization process.