Application of an in silico knockout model for gastrointestinal absorption of ketones using a systems pharmacology approach

Background: There is increasing evidence in recent years of the therapeutic benefits of induced mild ketosis in various neurological disorders. A novel means of achieving ketosis is by nutritional consumption of a ketone monoester ((R)-3-hydroxybutyl (R)-3-hydroxybutyrate) that hydrolyses to D-β-hydroxybutyrate (BHB).[1] The absorption of ketone monoester and BHB and its disposition appears to be complicated.[2]

Aim: Specific aims of this work include (1) develop a systems pharmacology model for gastrointestinal absorption of small molecules with an application to ketone monoester, (2) to explore mechanism of gastrointestinal absorption of ketones using in silico knockout variants of the systems model.

Methods: A literature search was conducted to identify and collate information on relevant processes: production, transport and regulation of ketones (dietary and endogenous) and factors governing these processes. Systems model components were: (i) luminal sites of gut with variability in expression of transporters in these sites, (ii) the portal and systemic circulation, (iii) the liver as the site of production of endogenous ketones, (iv) all other lumped organs/tissues that metabolise and excrete ketones. The model was developed as ordinary differential equations in MATLAB®. The model was then used to explore absorption mechanisms by developing knockout variants.

Results: A systems pharmacology model was developed by integrating information from the literature specifying metabolic pathways, transporters involved in the flux and the knowledge gained from the empirical model building.[2] Simulations from the systems model were able to provide a reasonable prediction of blood BHB profiles and were comparable to the empirical data. Knocking out specific processes and specific regions of the gut indicated that low dose was predominantly absorbed in the proximal gut by passive diffusion. In contrast to this, the high dose was absorbed from across all sites in the gut and this was mainly mediated by passive diffusion in the proximal gut and by active process in the distal gut.

Discussion: The current work has highlighted that while there is detailed information on metabolic fate of ketones, there is significant missing information on their transport. Exploration of knockout variants has indicated the likely contribution of the effect of administered dose of ester on absorption process of ketones in the gut. This study also provides some insight into the mechanism of absorption of ketone ester.

1. Clarke K. et al. (2012). Regul Toxicol Pharmacol. 63(3):401-408
2. Shivva et al. PAGANZ conference; University of Otago, Dunedin, NZ. 2014