Purpose(s)
We aimed to develop a whole-body physiologically based pharmacokinetic (PBPK) model characterizing interplay of OCTs and MATEs in intestine, liver and kidney to predict metformin DDIs with cimetidine, pyrimethamine, trimethoprim, ondansetron, rabeprazole and verapamil.
Method(s)
A whole-body PBPK model involving interplay of OCTs and MATEs in intestine, liver and kidney was developed to predict the disposition of metformin and perpetrators (cimetidine, pyrimethamine, trimethoprim, ondansetron, rabeprazole and verapamil) as well as metformin DDIs with these perpetrators in human. The predictions were compared with clinic observations.
Result(s)
Consistent with clinic observations, simulations showed that metformin plasma exposure increased when coadministration with perpetrators, while the predicted metformin distribution in hepatic decreased. Sensitivity analysis demonstrated that contributions of the tested factors to metformin DDI with cimetidine are gastrointestinal transit rate > inhibition of renal OCT2 ≈ inhibition of renal MATEs > inhibition of intestinal OCT3 > intestinal pH > inhibition of hepatic OCT1. Individual contributions of transporters to metformin disposition are renal OCT2 ≈ renal MATEs > intestinal OCT3 > hepatic OCT1 > intestinal PMAT.
Conclusion(s)
In conclusion, DDIs of metformin with perpetrators are attributed to integrated effects of inhibitions of these transporters.