Dose-independent pharmacokinetics of metformin in rats: Hepatic and gastrointestinal first-pass effects.
Pharmacokinetic parameters of metformin were evaluated after intravenous and oral administration (50, 100, and 200 mg/kg) in rats. The hepatic, gastric, and intestinal first-pass effects were also measured after intravenous, intraportal, intragastric, and intraduodenal administration (100 mg/kg) in rats. The total area under the plasma concentration-time curve from time zero to time infinity (AUC) values were dose-proportional after both intravenous and oral dose ranges studied. After oral administration (100 mg/kg), approximately 4.39% of oral dose was not absorbed and extent of absolute oral bioavailability (F) value was approximately 29.9%. The gastrointestinal first-pass effect of metformin was approximately 53.8% of oral dose in rats (the gastric and intestinal first-pass effects were approximately 23.1 and 30.7%, respectively), and the hepatic first-pass effect was approximately 27.1% after absorption into the portal vein. Since approximately 41.8% of oral metformin was absorbed into the portal vein, the value of 27.1% is equivalent to 11.3% of oral dose. The first-pass effects of metformin in the lung and heart were almost negligible in rats. The low F value of metformin in rats was mainly due to considerable gastrointestinal first-pass effects. The stability of metformin, distribution of metformin between plasma and blood cells, and factors affecting protein binding of metformin to 4% human serum albumin were also discussed.
Choi
Young H
YH
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Kwanak-Gu, Seoul 151-742, South Korea.
Kim
Sang G
SG
Lee
Myung G
MG
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001773:Blood Cells / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003956:Dialysis; D004064:Digestive System / Q000378:metabolism*; D004386:Duodenum / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D007441:Intubation, Gastrointestinal; D008099:Liver / Q000378:metabolism*; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011169:Portal Vein; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D012709:Serum Albumin / Q000378:metabolism; D014018:Tissue Distribution
D007004:Hypoglycemic Agents; D012709:Serum Albumin; D008687:Metformin