The Oral Bioavailability of Lurasidone is Impacted by Changes to the Gut Microbiome: Implications for Antipsychotic Therapy

Abstract

Atypical antipsychotics are crucial for the management of schizophrenia and bipolar disorder, yet they exhibit significant pharmacokinetic variability which leads to inconsistent therapeutic responses. This study investigates the hypothesis that gut microbiome composition critically influences the oral bioavailability of lurasidone, a poorly soluble weak base antipsychotic with pH-dependent solubility. To investigate this, male Sprague-Dawley rats underwent systematic gut microbiome manipulation through pretreatment with antibiotics or prebiotics (inulin) for 14 days prior to a single oral dose of lurasidone. Pharmacokinetic analysis of collected plasma samples revealed a significant 4.3-fold increase in lurasidone bioavailability following prebiotic pretreatment, compared to a control (no pretreatment) group. Conversely, lurasidone bioavailability was highly variable in rats with a depleted microbiome (i.e., antibiotic treatment group), with 80% of animals demonstrating lower bioavailability than the control group. Characterisation of gut microbiome composition and short-chain fatty acid (SCFA) concentrations demonstrated positive correlations between lurasidone bioavailability, microbial diversity, and SCFA levels, mediated by modulation of luminal pH. Elevated SCFA levels created a favourable environment for lurasidone solubilisation by lowering intestinal pH. These findings highlight the potential for optimising antipsychotic pharmacokinetics through personalised microbiome interventions. Furthermore, the correlation between SCFAs and lurasidone bioavailability suggests their potential as biomarkers for predicting inter-patient pharmacokinetic variability, particularly for poorly soluble weak bases. Thus, new avenues are opened for developing novel co-therapies and screening tools to enhance antipsychotic pharmacokinetic performance, potentially improving treatment outcomes for patients with schizophrenia and bipolar disorder. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/604016v2_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@7dac6borg.highwire.dtl.DTLVardef@c2cf1corg.highwire.dtl.DTLVardef@1ab5460org.highwire.dtl.DTLVardef@130ab14_HPS_FORMAT_FIGEXP M_FIG C_FIG