Modelling the Absorption of Metformin with Patients Post Gastric Bypass Surgery

Optimized In Silico Modeling of Drug Absorption after Gastric Bypass: The Case of Metformin

“…Their simulation shows a good fit to the observed plasma concentration [10], while other data suggest that the adaptation might not be the only reason for enhanced metformin exposure [12]. Unlike our compartmental model, Almukainzi et al created a PBPK model based on age and body weight, with permeability-limited tissues in addition to the inclusion of transporters such as OCTs and the PMAT [34]. Since we knew the body weight, the renal clearance, and the volume of distribution for the observed plasma concentration-time profiles before and after RYGB surgery [10], we could recreate a simulation using only the compartmental model, focusing on the segmental-dependent permeabilities for the remaining intestine.…”

“…Only 10% of metformin is absorbed transcellularly, which is regulated by transporters, and 90% is absorbed paracellularly [33]. Since the absorption by the PMAT accounts for only a small percentage of metformin absorption and the upregulation of transporters by increasing the transporter expression in GastroPlus TM showed no effect [34], we chose to exclude transporters from our model to focus on other possible reasons for the higher absorption after RYGB. (4) The last possible explanation was the small intestinal adaptation from villous hyperplasia.…”

“…Almukainzi et al analyzed the results of Padwal et al using the simulation software GastroPlus TM [34]. They created simulated post-surgery physiological conditions to assess which parameters may have caused the findings of Padwal et al Their study suggests that the bioavailability of metformin is increased as a result of adaptations by the body, expressed as enlarged pore size, porosity, and the absorptive area in the remaining parts of the intestine [34]. Their simulation shows a good fit to the observed plasma concentration [10], while other data suggest that the adaptation might not be the only reason for enhanced metformin exposure [12].…”

“…In the case of metformin, GastroPlus TM can make a close prediction only using these drug-specific segmental-dependent permeabilities without having to make further adjustments to the model. It seems that the program is able to adapt to the new physiology with just the known values, without changing the pore size, pore density, or the absorptive surface area [34]. Since it is unknown to what extent these adaptations occur, it is difficult and non-ideal to change these values.…”

“…Therefore, the paracellular permeability was included into GastroPlus TM simulations. The used paracellular model followed previously published reports [34]. In order to adjust the ratio between the paracellular/transcellular P eff to 90%:10%, the molecular radius was altered.…”