Effects of bacterial lipopolysaccharide on the pharmacokinetics of metformin in rats.
It was reported that the hepatic microsomal cytochrome P450 (CYP) 2C11, 2D1, and 3A1 (not via the CYP1A2, 2B1/2, and 2E1) were involved in the metabolism of metformin in rats. It was also reported that the expressions of CYP2C11 and 3A2 decreased in rats pretreated with Klebsiella pneumoniae lipopolysaccharide (KPLPS). Therefore, the pharmacokinetic parameters of metformin could be changed in rats pretreated with KPLPS. Hence, the pharmacokinetic parameters of metformin were compared after both intravenous and oral administration of the drug at a dose of 100mg/kg to control rats and rats pretreated with KPLPS. After intravenous administration of metformin to rats pretreated with KPLPS, the total area under the plasma concentration-time curve from time 0 to infinity (AUC) of the drug was significantly greater (40.5% increase) than the controls due to significantly smaller CL value (27.7% decrease) than the controls. The significantly smaller CL value could be due to significantly smaller both the CL(R) and CL(NR) values (34.0% and 18.1% decrease, respectively) than the controls. The significantly smaller CL(NR) value could be due to decrease in the expressions of CYP2C11 and 3A2 in rats pretreated with KPLPS. After oral administration of metformin, the AUC of the drug was not significantly different between two groups of rats, and this may be at least partly due to decrease in absorption from the gastrointestinal tract compared with the controls.
Choi
Young H
YH
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, South Korea.
Lee
Inchul
I
Lee
Myung G
MG
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001682:Biological Availability; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D015536:Down-Regulation; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D007408:Intestinal Absorption / Q000187:drug effects; D007711:Klebsiella pneumoniae / Q000737:chemistry; D008070:Lipopolysaccharides / Q000302:isolation & purification / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008687:Metformin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D039181:Steroid 16-alpha-Hydroxylase / Q000378:metabolism
D007004:Hypoglycemic Agents; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D008687:Metformin; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase