Predictive tools for the evaluation of microbial effects on drugs during gastrointestinal passage

Abstract

The impact of the gastrointestinal drug biotransformation on patients' health will grow with increasing complexity of drug entities. Predicting metabolic fates of drugs by combining in vitro and in silico models provides invaluable information which will be suitable to particularly reduce in vivo studies.

The Gut Microbiota as Target for Innovative Drug Development: Perspectives and a Case Study of Inflammatory Bowel Diseases

“…When using animals or humans in the screening processes, the lack of direct accessibility to study intestinal processes in the gut itself represents a serious obstacle to elucidate the importance of intestinal processes for a specific drug candidate. Moreover, whereas final in vivo testing is off course required to confirm formulation performance, this approach holds a number of drawbacks to be used in early stages of drug development such as ethical concerns, lack of information on the mechanism of action, analytical difficulties related to dilution of the active compounds and their metabolites in the plasma and the rest of the body as well as doubts on the representativeness of animal models for the human situation (Pieper & Bertau, 2010). In vitro simulation studies may offer many unique advantages, even if they suffer from the absence of a complete physiological environment.…”

“…stomach (secretion of gastric juice and simulation of fasted and fed condition); small intestine (secretion of pancreatic juice and bile salts, absorption of nutrients/electrolytes and high shear forces); large intestine (presence of a representative microbial community -in terms of activity and composition -in the ascending, transverse and descending colon); and finally, host-microbiota interaction (simulation of the final effect on the host). Among the several options available on the market, the TIM model (TNO, Delft, The Netherlands) and the SHIME ® (ProDigest and Ghent University, Gent, Belgium) are considered as being the most accurate imitations of the GIT both on a structural and a functional level (Pieper & Bertau, 2010). The TIM model is composed of two separate computer-controlled units -TIM 1 and 2 -running independently (Minekus & Havenaar, 1996;Minekus et al, 1999).…”

“…Whereas the TIM system appears nowadays as the most suitable simulator for the processes occurring in the upper GIT, the SHIME ® can provide more reliable results in terms of simulation of processes at the level of microbial metabolism. It has to be acknowledged that the simulation of absorption, which takes into account only diffusion, is limited in both systems, as well as the absence of a direct prediction of the possible effect of the treatment on the host (Pieper & Bertau, 2010). The coupling of these dynamic simulators with an "off-line" test system that makes use of Caco-2/HT 29 cell lines has been proposed as a possible approach to increase the scientific outcome of the in vitro simulation (Deat et al, 2009;Possemiers et al, 2011a).…”

“…These are normally considered as an alternative to the classical in vivo and in vitro studies. They make use of mathematical models to assess drug absorption, distribution, metabolism and excretion (Pieper & Bertau, 2010). The most commonly used models are the physiologically-based pharmacokinetics (Leahy, 2003), the systems biology-based drug metabolism simulation (Bugrim et al, 2004), the quantitative structure-activity relationship modelling (Chang & Swaan, 2006), and the computational oral absorption simulation (Sugano, 2009).…”

“…The most commonly used models are the physiologically-based pharmacokinetics (Leahy, 2003), the systems biology-based drug metabolism simulation (Bugrim et al, 2004), the quantitative structure-activity relationship modelling (Chang & Swaan, 2006), and the computational oral absorption simulation (Sugano, 2009). More specific information on the topic has been recently reviewed by Bertau et al (2008) and Pieper & Bertau (2010). A common trait of all these models is the fact they mainly focus on (hepatic) host metabolism, thereby omitting the role of the gut microbiota due to its extreme complexity and the lack of knowledge related to several metabolic processes occurring in the GIT.…”