OBJECTIVE: Use of gastric bypass surgery is common and increasing. Over 40% of patients in diabetes remission after gastric bypass surgery may redevelop diabetes within 5 years. Metformin, the first-line drug for diabetes, has low bioavailability and slow, incomplete gastrointestinal absorption. We hypothesized that gastric bypass would further reduce the absorption and bioavailability of metformin. RESEARCH DESIGN AND METHODS: In a nonblinded, single-dose pharmacokinetic study, 16 nondiabetic post–gastric bypass patients and 16 sex- and BMI-matched control subjects (mean age 40 years and BMI 39.2 kg/m2) were administered two 500-mg metformin tablets. Plasma metformin levels were sampled at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 h. Metformin absorption, estimated by the area under the curve (AUC) of the plasma drug concentrations from time 0 to infinity (AUC0-∞), was the primary outcome, and metformin bioavailability, assessed by measuring 24-h urine metformin levels, was a secondary outcome. RESULTS: Compared with control subjects, metformin AUC0–∞ was increased in gastric bypass subjects by 21% (13.7 vs. 11.4 μg/mL/h; mean difference 2.3 [95% CI −1.3 to 5.9]) and bioavailability was increased by 50% (41.8 vs. 27.8%; 14.0 [4.1–23.9]). Gastric bypass patients had significantly lower AUC glucose levels over 8 h compared with control subjects (35.8 vs. 41.7 μg/mL/h; 5.9 [3.1–8.8]), but this was likely a result of differences in baseline fasting glucose and not metformin absorption. CONCLUSIONS: Metformin absorption and bioavailability seem to be higher after gastric bypass, and this may have implications on dosing and toxicity risk. Studies are needed to confirm these findings and delineate potential mechanisms.

Introduction: Being overweight is widespread in most societies and represents a major health threat. Gastric bypass surgery offers a highly effective mode of treatment for the morbidly obese patients. The procedures cause an alteration in normal gastrointestinal anatomy and physiology, with consequences not only on nutrient absorption, but also possibly on orally administered drugs. Bypass of the acidic environment of the stomach, partial impairment of bile salts–drug interactions and reduced absorptive surface, all create the potential for reduced absorption of drugs. Areas covered: This article provides an overview of the effects of obesity and the most prevalent type of gastric bypass (Roux-en-Y) on pharmacokinetics. Articles for review were searched using Pubmed. Expert opinion: The absorption of those drugs with known bioavailability issues generally seem to be most affected by bypass surgery. It is important to consider the effect of obesity on pharmacokinetics independent of the bypass procedure, because it leads to a dramatic drop in body mass over a relatively short period of time. This may be associated with reversals in the influence of obesity on drug disposition to characteristics more in line with leaner patients. Drugs will differ in their pharmacokinetic response to surgery, limiting any general conclusions regarding the impact of the surgery on drug disposition.

Purpose: The induction of hyperlipidemia using poloxamer 407 (P407) is gaining use for studying the effect of the condition on drug pharmacokinetics. Although a single intraperitoneal dose of P407 causes a rapid onset of hyperlipidemia, the initial lipid concentrations are much higher than seen in humans. The hyperlipidemia is also reversible in nature. Here, pharmacokinetic methods were used to assess the P407 dose response on serum lipids, adipokines and cytokines. Methods: Single 0.5 and 1 g/kg doses of P407 were injected into rats followed by blood collection at various times for up to 12 d. Serum was assayed for lipids, selected adipokines and cytokines. Results: As expected, large increases in lipid levels were seen by 36 h after dosing. Using area under the concentration vs. time curve as a measure of systemic lipid exposure, P407 increased serum baseline corrected serum lipids in a nearly dose proportional fashion. The maximum increase in lipids was observed at ~36 h, with most lipids remaining elevated for up to ~180 h, although for the 1 g/kg dose triglyceride concentrations had still not quite returned to baseline by 12 days postdose. In addition to changes in lipids, P407 significantly increased serum leptin and decreased the serum adiponectin concentrations but did not affect cytokine levels. Conclusion: Depending on study aims, for the use of the model it may be beneficial to perform single-dose assessments at time points later than 36 h when the lipoprotein concentrations will be more similar to those seen in patient with hyperlipidemia. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.