Abstract
BackgroundThe role of the gut microbiome in the biotransformation of drugs has recently come under scrutiny. It remains unclear whether the gut microbiome directly influences the extent of drug absorbed after oral administration and thus potentially alters clinical pharmacokinetics. MethodsIn this study, we evaluated whether changes in the gut microbiota of male Sprague Dawley rats, as a result of either antibiotic or probiotic administration, influenced the oral bioavailability of two commonly prescribed antipsychotics, olanzapine and risperidone. FindingsThe bioavailability of olanzapine, was significantly increased (1.8-fold) in rats that had undergone antibiotic-induced depletion of gut microbiota, whereas the bioavailability of risperidone was unchanged. There was no direct effect of microbiota depletion on the expression of major CYP450 enzymes involved in the metabolism of either drug. However, the expression of UGT1A3 in the duodenum was significantly downregulated. The reduction in faecal enzymatic activity, observed during and after antibiotic administration, did not alter the ex vivo metabolism of olanzapine or risperidone. The relative abundance of Alistipes significantly correlated with the AUC of olanzapine but not risperidone. InterpretationAlistipes may play a role in the observed alterations in olanzapine pharmacokinetics. The gut microbiome might be an important variable determining the systemic bioavailability of orally administered olanzapine. Additional research exploring the potential implication of the gut microbiota on the clinical pharmacokinetics of olanzapine in humans is warranted. FundingThis research is supported by APC Microbiome Ireland, a research centre funded by Science Foundation Ireland (SFI), through the Irish Government's National Development Plan (grant no. 12/RC/2273 P2) and by Nature Research-Yakult (The Global Grants for Gut Health; Ref No. 626891).
Highlights
Research in contextEvidence before this studyDespite the growing evidence of a relationship between drugs and the gut microbiome, pharmacokinetic studies illustrating the potential clinical significance of such findings are still lacking
The marked difference between the antibiotic and the control group was detected at the genus level, with several genera being depleted in the antibiotic group (Fig. 2a)
Pharmacomicrobiomics is an emerging field that explores the effects of microbiome variations on drug pharmacokinetics and pharmacodynamics [37,38]
Summary
Research in contextEvidence before this studyDespite the growing evidence of a relationship between drugs and the gut microbiome, pharmacokinetic studies illustrating the potential clinical significance of such findings are still lacking. The study investigates if perturbations to the gut microbiota, induced by an antibiotic or probiotic mix, can translate to altered pharmacokinetics of olanzapine or risperidone in rats. This is the first pharmacokinetic study, to our knowledge, to explore microbiota-mediated metabolism of CNS-active drugs. Methods: In this study, we evaluated whether changes in the gut microbiota of male Sprague Dawley rats, as a result of either antibiotic or probiotic administration, influenced the oral bioavailability of two commonly prescribed antipsychotics, olanzapine and risperidone. Findings: The bioavailability of olanzapine, was significantly increased (1.8-fold) in rats that had undergone antibiotic-induced depletion of gut microbiota, whereas the bioavailability of risperidone was unchanged.
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