Pharmacokinetics of metformin in the rat: assessment of the effect of hyperlipidemia and evidence for its metabolism to guanylurea

Abstract

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 (iv). 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 iv doses as a consequence of short term hyperlipidemia, and a change in transporter mRNA but not protein expression in the 108 h post-P407 treated rats. 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.

Metformin Contamination in Global Waters: Biotic and Abiotic Transformation, Byproduct Generation and Toxicity, and Evaluation as a Pharmaceutical Indicator

“…In the U.S., metformin was the fourth most commonly prescribed medication, and prescriptions rose from 54.5 million in 2006 to 85.7 million in 2019 . Notably, unlike most pharmaceuticals, metformin is not metabolized in the human body by design, and almost all of the intake dose is excreted through urine and feces. , Thus, the widespread use has resulted in the frequent detection of metformin in global aquatic systems since 1999. , The demonstrated adverse effects for aquatic organisms make metformin a major contaminant of emerging concern, as reviewed elsewhere. ,− The environmental occurrence of metformin is attributable to its lack of metabolism in the human body and discharge through municipal wastewater treatment plants (WWTPs), , urban stormwater runoff, final landfill leachates, food process wastewater facilities, on-site septic systems, land application of municipal biosolids, etc. WWTPs cannot completely degrade metformin. , As a result, metformin and the generated transformation byproducts (TPs) are continuously discharged into aquatic systems and spread worldwide. ,, Metformin is also subject to transformation during natural processes and drinking water disinfection. − However, previous reviews mainly summarized the removal efficiency of metformin by different treatment methods but ignored the transformation pathways, TP generation, and whether such transformation would alleviate ecotoxicity.…”

“…8 Notably, unlike most pharmaceuticals, metformin is not metabolized in the human body by design, and almost all of the intake dose is excreted through urine and feces. 9,10 Thus, the widespread use has resulted in the frequent detection of metformin in global aquatic systems since 1999. 11,12 The demonstrated adverse effects for aquatic organisms make metformin a major contaminant of emerging concern, as reviewed elsewhere.…”

Assessment of glibenclamide pharmacokinetics in poloxamer 407-induced hyperlipidemic rats

“…A single dose of poloxamer-407 caused HL in rats; this model is an acceptable choice to evaluate the effect of HL in the pharmacokinetics of drugs, since it is non-inflammatory and not linked with diabetes or cardiovascular disruption ( Gabr et al, 2017 ).…”

Gualou Xiebai Banxia decoction ameliorates Poloxamer 407-induced hyperlipidemia

“…A partial or complete LPL deficiency results in an inability to hydrolyze TGs in chylomicrons and very low-density lipoproteins, causing mild to severe hypertriglyceridemia [6,7]. Poloxamer 407 (P407) has been shown to induce massive hyperlipidemia by directly inhibiting the heparin-releasable fraction of LPL [8,9]. Hyperlipidemia, which makes the liver more susceptible to damage, is the first step in hepatic lipid accumulation.…”