Prebiotic Supplementation Modulates the Gut Microbiome for Improving Oral Antipsychotic Bioavailability

Abstract

This study investigates the impact of gut microbiome composition on the bioavailability and biodistribution of lurasidone hydrochloride, an atypical antipsychotic used in treating mental health conditions. The research aims to uncover the relationship between gut metabolome, specifically short-chain fatty acids (SCFAs), and lurasidone absorption through modulation of intestinal pH. Male Sprague-Dawley rats underwent a 14-day microbiome depletion using antibiotics or prebiotics administered via drinking water, resulting in depleted, enriched, or normal (control) microbiomes. Following this treatment, lurasidone was orally administered to fasted rats, and blood samples were collected at specific intervals to correlate pharmacokinetic analysis with changes in microbiota and metabolome composition. Results revealed a significant 4.3-fold increase in lurasidone bioavailability following prebiotic administration, while antibiotic treatment decreased bioavailability. This effect is attributed to prebiotics increasing microbial diversity, which strongly correlates with SCFA production (R2 = 0.93). The subsequent lowering of intestinal pH created a more suitable environment for lurasidone solubility and absorption. This novel study establishes a clear relationship between gut microbiome composition and lurasidone bioavailability, with prebiotic administration positively impacting both gut microbial diversity and drug absorption. Thus, these findings suggest that gut microbiome manipulation may present an innovative approach to improving therapeutic outcomes for antipsychotic medications, potentially addressing poor response rates in some patients. Furthermore, this research highlights the importance of considering gut microbiome composition, in particular the use of SCFAs as a biomarker to produce predictive models of drug pharmacokinetics, especially for pH-dependent soluble drugs. In the context of drug efficacy these gut microbiome-based predictive pharmacokinetic models will pave the path for personalised medicine approaches for mental health treatment.