Effects of Escherichia coli lipopolysaccharide on the metformin pharmacokinetics in rats.
The time-dependent (2-h, 24-h, and 96-h) effects of Escherichia coli lipopolysaccharide (ECLPS) on the intravenous (100 mg kg(-1)) and oral (100 mg kg(-1)) metformin pharmacokinetics were evaluated in rats. After the intravenous administration of metformin to 24-h and 96-h ECLPS rats, the total area under the plasma concentration-time curve from time zero to time infinity (AUCs) and time-averaged non-renal clearances (CL(NR)s) of metformin were significantly greater and slower, respectively, than the controls. However, after the oral administration of metformin, the AUCs of metformin were comparable among four groups of rats. The greater (slower) intravenous AUCs (CL(NR)s) of metformin in 24-h and 96-h ECLPS rats were due to the slower hepatic intrinsic clearance (CL(int)) because of a decrease in the protein expression of hepatic cytochrome P450 (CYP) 2C11 and/or CYP3A subfamily than controls. The comparable oral AUCs among four groups of rats were mainly due to the comparable gastrointestinal metabolism (CL(int)).
Cho
Y K
YK
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.
Choi
Y H
YH
Kim
S H
SH
Lee
M G
MG
D000284:Administration, Oral; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D004926:Escherichia coli / Q000737:chemistry*; D007275:Injections, Intravenous; D007422:Intestines / Q000187:drug effects / Q000201:enzymology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D039181:Steroid 16-alpha-Hydroxylase / Q000378:metabolism; D013997:Time Factors
D001798:Blood Proteins; D008070:Lipopolysaccharides; D008687:Metformin; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase