While this eliminates the potential for DDIs involving hepatic metabolism as a mechanism, the discovery that PPIs interact with the OCT transporter system 1 raises issues about DDIs through several other plausible mechanisms, as this system appears to be involved in intestinal absorption, hepatic uptake and renal excretion of metformin 4. we found no evidence of a deleterious conversation between PPIs and metformin. study found that proton pump inhibitors (PPIs) at therapeutic concentrations can inhibit uptake of metformin into cells via the OCT1, OCT2 and OCT3 transporters 1. Since such inhibition could prevent metformin from reaching key target cells including hepatocytes, those authors hypothesized that PPIs may impair the glucose-lowering effect of metformin. Reviews of the potential for PPIs to interact with other drugs have layed out many potential mechanisms. The possibilities include alteration of drug absorption through changes in gastric pH and alteration of hepatic drug metabolism through CYP2C19 and other enzymes 2. Interactions with other CYP isoforms have been documented, and vary across different PPIs, making it possible that drugCdrug interactions (DDIs) may be specific to different PPIs 3. Metformin is not metabolized but rather excreted unchanged Amiloride HCl in the urine. While this eliminates the potential for DDIs involving hepatic metabolism as a mechanism, the discovery that PPIs interact with the OCT transporter system 1 raises concerns about DDIs through several other plausible mechanisms, as this system appears to be involved in intestinal absorption, hepatic uptake and renal excretion of metformin 4. The best-characterized of these effects is the OCT-1 transporter’s role in hepatic uptake of metformin. Impairment of its activity is associated with reduced distribution of metformin to the liver in both human and animal models 5,6. The liver is believed to be metformin’s principal site of action, and both knockout of OCT1 in mice and reduced-function genetic OCT1 variants in human volunteers are associated with significantly reduced effects of metformin on blood glucose 7. Two recent short term randomized crossover studies in healthy subjects found that co-administration of metformin with PPIs did not appear to alter metformin’s effect on glucose homeostasis, but did increase the area under the curve (AUC) of metformin’s plasma concentration by Amiloride HCl approximately 15% 8,9. The authors hypothesized that the modest increase Amiloride HCl in metformin plasma concentration might actually be due to inhibition of OCT transporters, which could reduce uptake into the liver and leave more drug in the plasma. While this study provided initial evidence that OCT transporter interaction with PPIs might not render metformin ineffective, the authors pointed out that further study was needed because these short term results in healthy volunteers did Amiloride HCl not necessarily apply to patients with diabetes mellitus. Further complicating the picture, PPIs have been proposed to have intrinsic glucose lowering properties of their own 10. This hypothesis was based on a small, cross-sectional observational study of patients with diabetes, in which patients who were taking a PPI had lower glycosylated haemoglobin (HbA1c) than those not taking one. In this instance, the epidemiological finding preceded any mechanistic investigation, but the authors proposed that PPIs may have insulin sensitizing properties. PPIs are among the most commonly used drugs and are taken by many patients with diabetes 11,12. Metformin is the first line drug for type 2 diabetes and is one of the most widely prescribed drugs in the Rabbit Polyclonal to BCAS3 world 13. If PPIs were to blunt the effectiveness of metformin, it could have a considerable impact on the care of diabetes worldwide. If PPIs actually were to have direct glucose lowering effects, that could also have clinical relevance, although with opposite implications. In this study, we aimed to conduct a pharmacoepidemiologic study of whether there Amiloride HCl is any evidence that an interaction of PPIs with metformin affects the most clinically relevant outcome, long-term glycaemic control, in patients with type 2 diabetes. Methods Study design We conducted a retrospective cohort study to test the primary hypothesis that there is an interaction between PPI exposure and metformin effectiveness as measured by HbA1c. A secondary goal was to assess whether PPIs had any direct effect on HbA1c. This was tested first by assessing whether there was any change in HbA1c when PPIs were initiated in patients who were.
Home » C3 » While this eliminates the potential for DDIs involving hepatic metabolism as a mechanism, the discovery that PPIs interact with the OCT transporter system 1 raises issues about DDIs through several other plausible mechanisms, as this system appears to be involved in intestinal absorption, hepatic uptake and renal excretion of metformin 4