Effect of altered gastric emptying and gastrointestinal motility on metformin absorption

Abstract

Aims The purpose of this in vivo human study was to assess the effect of altered gastric emptying and gastrointestinal motility on the absorption of metformin in healthy subjects. Methods An open-label, three treatment, three period crossover study was conducted in 11 healthy volunteers. Each subject received 550 mg metformin hydrochloride in solution alone; 5 min after a 10 mg i.v. dose of metoclopramide; and 30 min after a 30 mg oral dose of propantheline. Metformin solution was radiolabeled by the addition of 99m Tc-DTPA. The gastrointestinal transit of the solution was monitored by gamma scintigraphy and the pharmacokinetic data were correlated with the scintigraphic ®ndings. Results Scintigraphic data indicated that pretreatment with metoclopramide decreased gastric emptying time and increased gastrointestinal motility while pretreatment with propantheline had the opposite effect. The systemic disposition of metformin was not altered by pretreatment with metoclopramide and propantheline, as judged by unchanged renal clearance and elimination half-life of metformin. Extent of metformin absorption was essentially unchanged after pretreatment with metoclopramide. However, AUC(0,?) and % UR (percent dose excreted unchanged in urine) generally increased with increase in gastric emptying time and small intestinal transit times. GI overlay plots showed that the absorption phase of metformin plasma pro®le always coincided with gastric emptying and the beginning of decline of metformin plasma concentrations was usually associated with the colon arrival. Only in cases where the intestinal transit was drastically prolonged by propantheline pretreatment, was a decline in plasma levels observed prior to colon arrival. Conclusions Metformin is primarily absorbed from the small intestine. The extent of metformin absorption is improved when the gastrointestinal motility is slowed. These ®ndings have signi®cant implications in the design of a metformin modi®ed release dosage form.

Exploring gastrointestinal variables affecting drug and formulation behavior: Methodologies, challenges and opportunities

“…Previously, Marathe et al showed that the systemic availability of metformin, which is primarily absorbed in the small intestine, is significantly improved with delayed GE (Marathe et al, 2000). Oberle and Amidon linked the double peak phenomenon in plasma levels of cimetidine with the variable gastric emptying and transit along the intestinal tract combined with a short plasma elimination half-life and poor absorption (Oberle and Amidon, 1987).…”

Synthesis of fast swelling superporous hydrogel: effect of concentration of crosslinker and acdisol on swelling ratio and mechanical strength.

“…The absence of monomers was ensured spectrometrically by ensuring that the water of the washings did not contain any trace of monomers. The SPH was dried in an oven at 60°C for 6 hours [5][6][7][8].…”

Microparticulate and nanoparticulate drug delivery systems for metformin hydrochloride

“…Moreover, lactic acidosis, which is sometimes fatal, has occurred with biguanides (Sweetman, 2007). Development of novel formulation strategies for metformin might be useful to improve its bioavailability, to reduce the dosing frequency and to decrease gastrointestinal side effects and toxicity (Marathe et al, 2000;Cetin et al, 2013;Basavaraj & Betageri, 2014). Also, these systems may be helpful for effective use of metformin in cancer treatment (Alexis et al, 2010).…”