The rate and extent of absorption of metformin between post-RYGB subjects and matched control subjects was compared. Contrary to our hypothesis, the metformin bioavailability in RYGB subjects was significantly increased. Although the AUC0–8 h glucose level was significantly lower in bypass subjects compared with control subjects, this finding was likely explained by baseline differences in glucose levels and not differences in metformin absorption.
RYGB is considered by some to be procedure of choice in patients with type 2 diabetes because remission rates of type 2 diabetes are higher after RYGB compared with gastric banding (the other most commonly performed bariatric procedure). RYGB reduces average weight to a greater extent than gastric banding (43 vs. 29 kg) (13
) and leads to favorable neuroendocrine hormone-level alterations that correlate with improved glycemic control (14
). Currently, ~15% of patients undergoing bariatric surgery have type 2 diabetes, and one-quarter of these patients still require diabetes treatment immediately after surgery (13
). Nearly all patients remain clinically obese after surgery, and weight often is slowly regained postoperatively (15
). After 5 years, approximately 43% of diabetic patients in postoperative remission develop recurrence (10
). Therefore, assessing metformin absorption after bariatric surgery is of high clinical relevance because many patients will require continuation or reinitiation of metformin treatment postoperatively.
Metformin absorption is of clinical relevance because relationships have been observed between its plasma concentration and its glucose-lowering and glucose-regulating effects (9
). With respect to its biodisposition, metformin displays low and variable bioavailability, is not metabolized or excreted in bile, is 100% excreted in the urine, and has a short terminal half-life (4 h), meaning that nearly all of the bioavailable dose is eliminated within 24 h (7
). Therefore, unlike most drugs, 24-h urinary excretion can reliably estimate bioavailability without requiring intravenous administration. Based on its intrinsically low bioavailability and its apparent primary site for maximal absorption in the proximal small intestine, which possesses the largest overall surface area per unit length of the entire gut (16
), we theorized that absorption would be diminished after RYGB, a procedure that bypasses the proximal small intestine. The results provided several unexpected outcomes, including not only increased bioavailability but also increases in volume of distribution and renal clearance.
For the increase in the extent of absorption, several potential mechanisms may explain the results, including the following:
- RYGB performed with pouch volumes of 60–80 mL seems to delay gastric emptying for solid foods (17). In addition, RYGB increases intestinal transit time (18,19). Although data examining more contemporary pouch sizes (30 mL) and pills rather than food are lacking, we speculate that these gastrointestinal alterations may increase the overall absorption of metformin by increasing the duration of exposure of the drug to small-intestinal mucosa. The absorption of metformin is permeability rate limited, and the drug is almost exclusively absorbed in the small intestine (6,7,9). The drug that reaches the colon is not absorbed and is fecally excreted, with ~30% of the drug being eliminated in this manner (6). Because metformin has a limited window for absorption and absorption is incomplete, prolonging the intestinal transit time increases absorption (20). Similarly, delaying gastric emptying may decrease the rate at which the drug enters the small bowel, thus preventing saturation of absorptive mechanisms and increasing overall absorption (18). Slow-release formulations of metformin act in an analogous manner; the drug is physically retained in the stomach and released gradually into the upper small bowel, resulting in sustained and prolonged steady-state metformin levels (21).
- After RYGB, the newly created 20- to 30-mL gastric pouch is largely devoid of acid-producing cells, and acid secretion is virtually absent (22). Although this more alkaline environment may potentially enhance the solubility of an acidic drug, metformin is a base, with a pKa of 12.4–13.8 and is almost completely ionized at all ranges of intestinal pH (23). Therefore, increases in intestinal pH are unlikely to play a major role in increasing metformin absorption after bypass.
- Metformin is a substrate for organic cation transporters (OCTs), examples of which include human OCTs 1 and 2 (hOCT1 and -2), which are primarily found in the liver and kidney, and plasma membrane monoamine transporter in the intestine (23). Absorption in the intestinal tract appears to occur both transcellularly, which appears dependent upon OCTs (23), and paracellularly, which occurs via facilitated diffusion and may account for up to 90% of absorption (24). We speculate that alterations in these transport mechanisms, such as transporter upregulation, may be occurring after surgery, which may explain our findings.
- Small-intestinal adaptation resulting from villous hyperplasia and possibly related to increased luminal nutrient exposure is a phenomenon that has been described after bowel resection (24). In theory, a similar mechanism may occur after gastric bypass, although this has not been previously described in this patient population.
We documented a 50% increase in the bioavailability of metformin, which is large enough to be potentially clinically relevant, particularly if sustained with chronic dosing and especially in the presence of renal dysfunction. We did not find a relationship between increased absorption and reduced AUC glucose levels, but this was not unexpected. Previous studies have demonstrated that metformin has little effect on glucose levels in nondiabetic patients unless toxic levels of the drug are administered (7
). Furthermore, even in diabetic subjects, single doses of metformin have no effect on preprandial glucose and doses >1,700 mg are required to affect postprandial glucose levels (9
). Therefore, a notable effect on glucose levels would not be expected after administration of a single dose to nondiabetic subjects even if bioavailability increased by >50%.
In addition to the increase in oral bioavailability, higher metformin volume of distribution and renal clearance values in the surgical patients were found. The current study was not designed to provide insight into mechanisms underlying these interesting observations. It was apparent that the creatinine plasma concentrations and clearances were highly similar in the two groups (). Because metformin has low plasma protein binding and is efficiently renally secreted, the difference in renal clearance in the surgical patients may be a consequence of more efficient secretion, perhaps mediated by OCT2.
A limitation of our study was that a single dose was administered to fasting subjects. Fasting subjects were studied to minimize the effect of food on metformin absorption (food decreases absorption by ~25%) (25
). Although single-dose studies are easier to perform and are typically used to gain initial insight into an area, they have the drawback of not being able to assess steady-state levels. In clinical practice, multiple doses of metformin typically are administered with food. Thus, additional study examining steady-state levels in nonfasting subjects would be required to more closely mimic clinical practice. An additional limitation to our study was that nonsignificant differences in body weight and significant differences in metabolic parameters, including fasting glucose levels, were present at baseline. We also cannot rule out the possibility that secondary metabolic changes in unmeasured parameters occurring after gastric bypass (e.g., thyroid hormone alterations) influenced our results. In our analysis, adjustment for body weight was performed for relevant pharmacokinetic parameters and results were unchanged. Because metformin absorption does not vary according to diabetes status (7
), the baseline between-group differences in glucose levels are unlikely to explain our findings regarding metformin bioavailability. A post hoc analysis examining between-group differences in bioavailability corrected for baseline glucose levels did not change the results (9.6 vs. 5.4% · L/mmol; mean difference −4.2 [95% CI −2.0 to −6.5]).
In conclusion, metformin absorption and bioavailability were unexpectedly increased in gastric bypass subjects compared with control subjects. Therefore, factors other than diminished small-bowel length influence overall metformin absorption. This has potential implications for metformin dosing after bypass and for medications with similar pharmacological properties. Studies are needed to confirm these findings and delineate potential mechanisms.