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

A mouse study (C57BL/6N) investigated how acute inflammation induced by lipopolysaccharide (LPS; endotoxemia) alters the pharmacokinetics of olanzapine and its metabolite desmethyl-olanzapine (DMO). After a single oral dose of olanzapine, endotoxemia markedly increased exposure: olanzapine AUC rose ~3.8-fold in plasma and ~5.2-fold in brain. Mechanistically, the effect was driven mainly by increased absolute bioavailability (about +200%), with additional contributions from reduced plasma clearance (~34% decrease) and enhanced brain penetration of the unbound drug (Kp,uu,brain 6.2 vs 4.1). LPS suppressed hepatic Cyp1a2 expression and reduced the formation of DMO from olanzapine; however, systemic DMO concentrations increased substantially due to a pronounced reduction in DMO clearance. Importantly, DMO showed minimal brain penetration. The authors conclude that during acute infection/inflammation, central nervous system exposure to olanzapine may “overshoot,” potentially increasing adverse effects, and they highlight the potential value of therapeutic drug monitoring in such settings.