Detail
Článek
Článek online
FT
Medvik - BMČ
  • Je něco špatně v tomto záznamu ?

Acute inflammation induced by the Escherichia coli lipopolysaccharide considerably increases the systemic and brain exposure of olanzapine after oral administration in mice

J. Hubeňák, M. Mžik, H. Laštůvková, D. Bayer, L. Jandová, J. Schreiberová, C. Andrýs, S. Mičuda, J. Masopust, J. Chládek

. 2025 ; 28 (6) : . [pub] 20250606

Jazyk angličtina Země Anglie, Velká Británie

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc25015356

Grantová podpora
00179906 Ministry of Education, Youth, and Sports of the Czech Republic
University of Hradec Králové
Charles Universit

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.

Citace poskytuje Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc25015356
003      
CZ-PrNML
005      
20250731090926.0
007      
ta
008      
250708s2025 enk f 000 0|eng||
009      
AR
024    7_
$a 10.1093/ijnp/pyaf036 $2 doi
035    __
$a (PubMed)40411815
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a enk
100    1_
$a Hubeňák, Jan $u Department of Psychiatry, University Hospital and the Faculty of Medicine, Charles University, Hradec Kralove, Czech Republic
245    10
$a Acute inflammation induced by the Escherichia coli lipopolysaccharide considerably increases the systemic and brain exposure of olanzapine after oral administration in mice / $c J. Hubeňák, M. Mžik, H. Laštůvková, D. Bayer, L. Jandová, J. Schreiberová, C. Andrýs, S. Mičuda, J. Masopust, J. Chládek
520    9_
$a 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.
650    _2
$a zvířata $7 D000818
650    _2
$a olanzapin $x farmakokinetika $7 D000077152
650    _2
$a lipopolysacharidy $7 D008070
650    12
$a mozek $x metabolismus $x účinky léků $7 D001921
650    _2
$a aplikace orální $7 D000284
650    _2
$a myši inbrední C57BL $7 D008810
650    _2
$a mužské pohlaví $7 D008297
650    12
$a benzodiazepiny $x farmakokinetika $x krev $x aplikace a dávkování $7 D001569
650    12
$a antipsychotika $x farmakokinetika $x krev $x aplikace a dávkování $7 D014150
650    _2
$a myši $7 D051379
650    12
$a zánět $x chemicky indukované $x metabolismus $7 D007249
650    12
$a endotoxemie $x metabolismus $x chemicky indukované $7 D019446
655    _2
$a časopisecké články $7 D016428
700    1_
$a Mžik, Martin $u Department of Clinical Biochemistry and Diagnostics, University Hospital and the Faculty of Medicine, Charles University, Hradec Kralove, Czech Republic
700    1_
$a Laštůvková, Hana $u Department of Pharmacology, Faculty of Medicine, Charles University, Hradec Kralove, Czech Republic
700    1_
$a Bayer, David $u Department of Psychiatry, University Hospital and the Faculty of Medicine, Charles University, Hradec Kralove, Czech Republic
700    1_
$a Jandová, Lenka $u Faculty Vivarium, Faculty of Medicine, Charles University, Hradec Kralove, Czech Republic
700    1_
$a Schreiberová, Jolana $u Department of Pharmacology, Faculty of Medicine, Charles University, Hradec Kralove, Czech Republic
700    1_
$a Andrýs, Ctirad $u Department of Clinical Immunology and Allergology, University Hospital and the Faculty of Medicine, Charles University, Hradec Kralove, Czech Republic
700    1_
$a Mičuda, Stanislav $u Department of Pharmacology, Faculty of Medicine, Charles University, Hradec Kralove, Czech Republic
700    1_
$a Masopust, Jiří $u Department of Psychiatry, University Hospital and the Faculty of Medicine, Charles University, Hradec Kralove, Czech Republic
700    1_
$a Chládek, Jaroslav $u Department of Pharmacology, Faculty of Medicine, Charles University, Hradec Kralove, Czech Republic $1 https://orcid.org/0000000290526318 $7 xx0057856
773    0_
$w MED00176777 $t International journal of neuropsychopharmacology $x 1469-5111 $g Roč. 28, č. 6 (2025)
856    41
$u https://pubmed.ncbi.nlm.nih.gov/40411815 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y - $z 0
990    __
$a 20250708 $b ABA008
991    __
$a 20250731090921 $b ABA008
999    __
$a ok $b bmc $g 2366289 $s 1252481
BAS    __
$a 3
BAS    __
$a PreBMC-MEDLINE
BMC    __
$a 2025 $b 28 $c 6 $e 20250606 $i 1469-5111 $m International journal of neuropsychopharmacology $n Int J Neuropsychopharmacol $x MED00176777
GRA    __
$a 00179906 $p Ministry of Education, Youth, and Sports of the Czech Republic
GRA    __
$p University of Hradec Králové
GRA    __
$p Charles Universit
LZP    __
$a Pubmed-20250708

Najít záznam

Citační ukazatele

Možnosti archivace