Effect of altered gastric emptying and gastrointestinal motility on metformin absorption

Aims The purpose of this in vivo human study was to assess the effect of al tered gastric emptying and gastrointestinal motility on the absorption of m etformin in healthy subjects. Methods An open-label, three treatment, three period crossover study was co nducted in 11 healthy volunteers. Each subject received 550 mg metformin hy drochloride in solution alone; 5 min after a 10 mg i.v. dose of metoclopram ide; and 30 min after a 30 mg oral dose of propantheline. Metformin solutio n was radiolabeled by the addition of Tc-99m-DTPA. The gastrointestinal tra nsit of the solution was monitored by gamma scintigraphy and the pharmacoki netic data were correlated with the scintigraphic findings. Results Scintigraphic data indicated that pretreatment with metoclopramide decreased gastric emptying time and increased gastrointestinal motility whi le pretreatment with propantheline had the opposite effect. The systemic di sposition of metformin was not altered by pretreatment with metoclopramide and propantheline, as judged by unchanged renal clearance and elimination h alf-life of metformin. Extent of metformin absorption was essentially uncha nged after pretreatment with metoclopramide. However, AUC(0,infinity) and % UR (percent dose excreted unchanged in urine) generally increased with inc rease in gastric emptying time and small intestinal transit times. GI overl ay plots showed that the absorption phase of metformin plasma profile alway s 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 propanth eline pretreatment, was a decline in plasma levels observed prior to colon arrival. Conclusions Metformin is primarily absorbed from the small intestine. The e xtent of metformin absorption is improved when the gastrointestinal motilit y is slowed. These findings have significant implications in the design of a metformin modified release dosage form.