Title : Impact of gut microbiota-mediated bile acid metabolism on the solubilization capacity of bile salt micelles and drug biopharmaceutical properties
Abstract:
The symbiotic cohabitation of man and microbe has gained increasing recognition as a determinant of the health status of the human host, affording new insights into disease pathogenesis, as well as novel therapeutic targets. From an oral drug delivery perspective, pharmacokinetic research at the host-microbe interface has, to date, been largely concentrated on effects on drug metabolism. The objective of this oral presentation is to provide overview possible mechanisms by which the activity of the gut microbiota might influence the drug absorption process, for example by modulating passive uptake. In the gastrointestinal lumen, bile salts produced by the host are biotransformed by the gut bacteria. This gut microbiota-mediated bile acid metabolism may, by virtue of altering the bile acid pool, affect intraluminal drug solubility and consequently drug absorption.
To discuss the possible impact of bile acid metabolism on intraluminal drug solubility, in vitro data comparing the solubilization capacity of host- versus microbe- derived bile salt micelles for 9 drugs will be presented. Briefly, this data indicates that deconjugation of the bile acid steroidal core (mediated by microbial bile salt hydrolase in vivo) could marginally affect micellar solubilization capacity for some poorly water-soluble drugs (PWSDs). Contrastingly, dehydroxylation of the bile acid nucleus (microbial 7α-dehydroxylase activity) resulted in a statistically significant difference (p < 0.05) in bile micelle solubilization capacity; an effect which was observed for all of the model PWSDs tested (Figure 1.). The different magnitudes of solubility enhancement observed for these PWSDs will be discussed with respect to 3 physicochemical descriptors, namely Log P, melting point and polar surface area. In order to progress the physiological relevance of these findings, solubility, dissolution and preliminary permeability data in biorelevant media containing host- versus microbe- derived bile acids will additionally be presented and discussed.
In conclusion, potential mechanisms (identified in vitro) by which the gut microbiota might affect the drug absorption process and thereby drug activity will be presented. Should these findings translate in vivo, disruption of the gut microbial ecosystem could contribute to altered drug solubilization and absorption amongst patient cohorts.
Figure 1. Solubilization capacity of primary (host- derived taurocholic acid (TCA)) versus secondary (microbe-derived taurodeoxycholic acid (TDCA)) bile salt micelles for a selection of PWSDs (n = 3, mean ± SD). The magnitude of solubility enhancement in dehydroxylated microbe-derived (TDCA) bile salt micelles was found to be strongly correlated with PWSD lipophilicity (LogP).
Learning objectives
• To differentiate between host- and microbe- derived bile acids and to gain an appreciation of their altered physicochemical properties.
• To identify the key physicochemical descriptors influencing the differential solubilization of PWSDs by host- and microbe- derived bile salt micelles.
• To discuss the potential significance of altered bile acid “signatures” in the context of biopharmaceutical oral dosage form assessment.
Takeaway Notes:
• The aim of the outlined oral presentation is to provide an insight into the possible mechanisms by which the gut microbiota may affect PWSD solubility, dissolution and permeability. It is envisaged that this topical subject matter will stimulate discussions regarding the need to consider the processes of the gut microbiota, as well as the target subject, the human host.
• The audience is also expected to benefit from discussion regarding a design-of-experiment approach to establishing an in vitro model to assess the impact of different bile salts on drug permeability/activity, which could be used to address other scientific questions.
