Acute inflammation induced by the Escherichia coli lipopolysaccharide considerably increases the systemic and brain exposure of olanzapine after oral administration in mice
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00179906%3A_____%2F25%3A10499749" target="_blank" >RIV/00179906:_____/25:10499749 - isvavai.cz</a>
Alternative codes found
RIV/00216208:11150/25:10499749
Result on the web
<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=XwDHkEH0Qd" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=XwDHkEH0Qd</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1093/ijnp/pyaf036" target="_blank" >10.1093/ijnp/pyaf036</a>
Alternative languages
Result language
angličtina
Original language name
Acute inflammation induced by the Escherichia coli lipopolysaccharide considerably increases the systemic and brain exposure of olanzapine after oral administration in mice
Original language description
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.
Czech name
—
Czech description
—
Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
—
OECD FORD branch
30104 - Pharmacology and pharmacy
Result continuities
Project
<a href="/en/project/EH22_008%2F0004607" target="_blank" >EH22_008/0004607: New Technologies for Translational Research in Pharmaceutical Sciences /NETPHARM</a><br>
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2025
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
International Journal of Neuropsychopharmacology
ISSN
1461-1457
e-ISSN
1469-5111
Volume of the periodical
28
Issue of the periodical within the volume
6
Country of publishing house
GB - UNITED KINGDOM
Number of pages
11
Pages from-to
pyaf036
UT code for WoS article
001517316700001
EID of the result in the Scopus database
2-s2.0-105009388482