Intestinal permeability of metformin using single-pass intestinal perfusion in rats.
OBJECTIVE
To characterize the intestinal transport and mechanism of metformin in rats and to investigate whether or not metformin is a substrate for P-glycoprotein (P-gp).


METHODS
The effective intestinal permeability of metformin was investigated using single-pass intestinal perfusion (SPIP) technique in male Waster rats. SPIP was performed in three isolated intestinal segments (duodenum, jejunum and ileum) at the same concentration of metformin (50 microg/mL) to test if the intestinal transport of metformin exhibited site-dependent changes, and in a same isolated intestinal segment (duodenal segment) at three different concentrations of metformin (10, 50, 200 microg/mL) to test if the intestinal transport of metformin exhibited concentration-dependent changes. Besides, P-gp inhibitor verapamil (400 microg/mL) was co-perfused with metformin (50 microg/mL) in the duodenum segment to find out if the intestinal absorption of metformin was affected by P-gp exiting along the gastrointestinal track. Stability studies were conducted to ensure that the loss of metformin could be attributed to intestinal absorption.


RESULTS
The effective permeability values (P(eff)) of metformin in the jejunum and ileum at 50 microg/mL were significantly lower than those in the duodenum at the same concentration. Besides, P(eff) values in the duodenum at high concentration (200 microg/mL) were found to be significantly lower than those at low and medium concentrations (10 and 50 microg/mL). Moreover the co-perfusion with verapamil did not increase the P(eff) value of metformin at 50 microg/mL in the duodenum.


CONCLUSIONS
Metformin could be absorbed from the whole intestine, with the main absorption site at duodenum. This concentration-dependent permeability behavior in the duodenum indicates that metformin is transported by both passive and active carrier-mediated saturable mechanism. The P(eff) value can not be increased by co-perfusion with verapamil, indicating that absorption of metformin is not efficiently transported by P-gp in the gut wall. Furthermore metformin is neither a substrate nor an inducer of P-gp. Based on the P(eff) values obtained in the present study and using established relationships, the human fraction dose absorbed for metformin is estimated to be 74%-90% along human intestine.
Song
Nai-Ning
NN
School of Chemical Engineering and Technology, Tianjin University, China.
Li
Quan-Sheng
QS
Liu
Chang-Xiao
CX
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007408:Intestinal Absorption / Q000187:drug effects; D007421:Intestine, Small / Q000378:metabolism*; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010477:Perfusion / Q000379:methods; D010539:Permeability; D051381:Rats; D017208:Rats, Wistar
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007004:Hypoglycemic Agents; D008687:Metformin