Pharmacokinetics of metformin in the rat: assessment of the effect of hyperlipidemia and evidence for its metabolism to guanylurea.
Metformin pharmacokinetics are highly dependent upon organic cationic transporters. There is evidence of a change in its renal clearance in hyperlipidemic obese patients, and no information on its metabolic fate. To study some of these aspects, the influence of poloxamer 407 (P407)-induced hyperlipidemia on metformin pharmacokinetics was assessed. Control and P407-treated adult male rats were administered 30 mg/kg metformin intravenously (i.v.). The pharmacokinetic assessments were performed at 2 time points, 36 and 108 h, following the intraperitoneal dose of P407 (1 g/kg). mRNA and protein expressions of cationic drug transporters were also measured. There was no evidence of a change in metformin pharmacokinetics after i.v. doses as a consequence of short-term hyperlipidemia, and a change in transporter mRNA but not protein expression was observed in the P407- treated rats 108 h after P407 injection. Urinary recovery of unchanged drug was high (>90%) but incomplete. Presumed metabolite peaks were detected in chromatograms of hepatocytes and microsomal protein spiked with metformin. Comparative chromatographic elution times and mass spectra suggested that one of the predominant metabolites was guanylurea. Hyperlipidemia by itself did not affect the pharmacokinetics of metformin. Guanylurea is a putative metabolite of metformin in rats.
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2E1, Canada.
Raniah Q
RQ
Gabr
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2E1, Canada.|Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2E1, Canada.
Ahmed A
AA
El-Sherbeni
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2E1, Canada.|Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2E1, Canada.
Mohamed
M
Ben-Eltriki
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2E1, Canada.|Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2E1, Canada.
Ayman O
AO
El-Kadi
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2E1, Canada.|Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2E1, Canada.
Dion R
DR
Brocks
D000818:Animals; D017920:Antiporters / Q000378:metabolism; D050482:Catecholamine Plasma Membrane Transport Proteins / Q000378:metabolism; D006146:Guanidines / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006949:Hyperlipidemias / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D027701:Organic Cation Transport Proteins / Q000378:metabolism; D000075102:Organic Cation Transporter 2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014508:Urea / Q000031:analogs & derivatives* / Q000378:metabolism
D017920:Antiporters; D050482:Catecholamine Plasma Membrane Transport Proteins; D006146:Guanidines; C587327:N-guanylurea; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; C493212:Slc22a1 protein, rat; C515734:Slc47a1 protein, rat; D014508:Urea; D008687:Metformin
biguanides; mass spectroscopy; organic cation transporters; poloxamer 407; poloxamère 407; spectroscopie de masse; transporteurs cationiques organiques