BACKGROUND: A detailed understanding of alterations in olanzapine pharmacokinetics during acute inflammatory states, associated with infections, remains lacking. This study aimed to investigate the impact of endotoxemia on the pharmacokinetics of olanzapine and desmethylolanzapine (DMO) in mice. METHODS: C57BL/6N mice received an intraperitoneal injection of lipopolysaccharide (LPS, 5 mg/kg) or saline (controls), followed 24 hours later by single oral or intravenous doses of olanzapine or intravenous DMO. Concentrations and unbound fractions of olanzapine and DMO were measured in the plasma and brain homogenates. RESULTS: In LPS-injected mice, the area under the concentration-time curve (AUCs) for olanzapine increased 3.8-fold in the plasma and 5.2-fold in brain homogenates, in consequence of a higher absolute bioavailability of olanzapine (+200%), a lower plasma clearance (-34%), and a higher brain penetration ratio for the unbound drug relative to controls (Kp,uu,brain 6.2 vs. 4.1). LPS attenuated the hepatic mRNA expression of cytochrome P450 1A2 and the metabolism of olanzapine to DMO. However, the AUC of plasma DMO increased by 140% due to a 4.8-fold decrease in the plasma clearance of DMO. The brain penetration of DMO was minimal (Kp,uu,brain ≤ 0.051). The LPS-injected mice exhibited a downregulation of the hepatic and ileal mRNA expression of P-glycoprotein (Abcb1a), whereas the expression of Abcb1a and Abcb1b in the brain was upregulated. CONCLUSIONS: Endotoxemia notably increases olanzapine concentrations in the plasma and brain following oral administration in mice. Further studies should clarify whether altered pharmacokinetics results in adverse effects in acutely infected patients taking oral olanzapine.

• Klíčová slova
• brain penetration, endotoxemia, lipopolysaccharide, olanzapine, pharmacokinetics,
• MeSH
• antipsychotika * farmakokinetika   krev   aplikace a dávkování   MeSH
• aplikace orální MeSH
• benzodiazepiny * farmakokinetika   krev   aplikace a dávkování   MeSH
• endotoxemie * metabolismus   chemicky indukované   MeSH
• lipopolysacharidy MeSH
• mozek * metabolismus   účinky léků   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• olanzapin farmakokinetika   MeSH
• zánět * chemicky indukované   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antipsychotika * MeSH
• benzodiazepiny * MeSH
• lipopolysacharidy MeSH
• olanzapin MeSH

A novel non-aqueous capillary electrophoresis - tandem mass spectrometry method for the simultaneous separation, identification and quantification of nine designer benzodiazepines (bentazepam, etizolam, deschloroetizolam, diclazepam, flubromazepam, flubromazolam, nimetazepam, phenazepam, and pyrazolam) was developed. A non-aqueous running electrolyte consisting of 25mM ammonium acetate with 100mM trifluoroacetic acid in acetonitrile was used. The separation was carried out using a semipermanent coated capillary (successive multiple ionic-polymer coating) with a strong anodic electroosmotic flow at a negative separation voltage within twelve minutes. Electrospray ionization with a triple quadrupole mass spectrometry was utilized for the identification and quantification of selected designer benzodiazepines in a positive ionization mode. The developed method was validated and applied on the analysis of spiked serum sample following a simple liquid-liquid extraction. The LODs of the designer benzodiazepines were between 1.5 and 15.0ngmL-1.

• Klíčová slova
• Benzodiazepine, Capillary electrophoresis, Designer drug, Mass spectrometry, Nonaqueous electrolyte, Toxicological analysis,
• MeSH
• benzodiazepiny krev   MeSH
• elektroforéza kapilární MeSH
• extrakce kapalina-kapalina MeSH
• hexadimethrin bromid chemie   MeSH
• hmotnostní spektrometrie s elektrosprejovou ionizací MeSH
• lidé MeSH
• limita detekce MeSH
• nové syntetické drogy analýza   MeSH
• tandemová hmotnostní spektrometrie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• benzodiazepiny MeSH
• hexadimethrin bromid MeSH
• nové syntetické drogy MeSH

A new ultra high performance liquid chromatography with electrospray ionization time of flight mass spectrometry method for the selective and sensitive separation, identification, and determination of selected designer benzodiazepines (namely, pyrazolam, phenazepam, etizolam, flubromazepam, diclazepam, deschloroetizolam, bentazepam, nimetazepam, and flubromazolam) in human serum was developed. The separation of the studied designer benzodiazepines was achieved on C18 chromatographic column using gradient elution within 6 min without any significant matrix interferences. Liquid-liquid extraction with butyl acetate was applied for serum samples cleanup and preconcentration of studied designer benzodiazepines. The method was validated in terms of linearity, limit of detection, limit of quantification, matrix effects, specificity, precision, accuracy, recovery, and sample stability. The limit of detection values were 0.10-0.15 ng/mL. The method was applied to a spiked serum sample to demonstrate its applicability for systematic toxicology analysis. Furthermore, a capillary chromatographic method with micellar electrokinetic chromatography was used for the estimation of partition coefficients of studied designer benzodiazepines as important parameters to evaluate their pharmacological and toxicological properties.

• Klíčová slova
• benzodiazepines, liquid chromatography, mass spectrometry, micellar electrokinetic chromatography, partition coefficients,
• MeSH
• benzodiazepiny krev   MeSH
• hmotnostní spektrometrie s elektrosprejovou ionizací * MeSH
• lidé MeSH
• limita detekce MeSH
• micely MeSH
• reprodukovatelnost výsledků MeSH
• vysokoúčinná kapalinová chromatografie * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• benzodiazepiny MeSH
• micely MeSH