Furfural drug safety: Metabolite check on hydroxymethylfurfural in humans

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  • Published: Mar 19, 2013
  • Author: Steve Down
  • Channels: HPLC
thumbnail image: Furfural drug safety: Metabolite check on hydroxymethylfurfural in humans

Antioxidant furfurals

The metabolism of the antioxidant and potential anti-cancer drug 5-hydroxymethylfurfural has been studied by HPLC with a HILIC column, revealing the absence of a potentially toxic metabolite.


The simple compound 5-hydroxymethylfurfural (HMF) occurs in many processed foodstuffs and is attracting attention as a potential anti-cancer drug. It is formed as a product of the so-called Maillard reaction that is initiated by heating or sterilisation and causes browning in foods. The carbonyl groups of sugars react with the amino groups in proteins and HMF is one of the potential final products.

It is the antioxidative nature of HMF that is exciting, mopping up free radicals in the body and protecting against hypoxia and it is currently undergoing Phase II trials for cancer therapy. However, despite numerous studies on its metabolism in animals and humans, there remains some doubt about the range of potential metabolites.

Martin Schmid and colleagues from the Karl-Franzens University Graz and the Medicinal University Graz were concerned about the 5-sulphoxymethylfurfural (SMF) which has been reported as a metabolite of HMF in rodents. There are mixed reports about its toxicity and mutagenicity in rats, so it needs to be investigated in humans too to ensure the safety of HMF.

In a study published in 2012, Schmid developed an HPLC method for measuring the various metabolites of HMF and now it has been applied to the metabolism of the drug in humans, to identify as many metabolites as possible. The findings were reported in the Journal of Separation Science.

Help from HILIC

In the first instance, the chromatographic properties of the potential metabolites were ascertained from the standard compounds. A mixture of HMF, 5-hydroxymethylfuroic acid (HMFA), 2,5-furandicarboxylic acid (FDCA), the conjugate N-(5-hydroxymethyl)furoylglycine (HMFG) and SMF was prepared, also containing 5-methylfurfural and 3,4-dimethoxy-2,5-furandicarboxylic acid as internal standards.

The mixture was injected onto an HILIC column and the compounds were eluted within 15 minutes with an increasing gradient of acidic ammonium formate in acetonitrile. Good separation was achieved for them all, although HMF and MF eluted close to each other. With a UV detector operating at 265 nm, the detection and quantitation limits were 55-260 and 70-970 ng/mL, respectively.  

The optimised method was tested on the urines of two healthy male nonsmokers and one female suffering from ovarian cancer and metastases. They were all given a single oral dose of Sanopal, a medication containing HMF. The urines were collected over 48 hours and cleaned up by SPE during which the two internal standards were added.

Toxic metabolites absent

The major metabolite was found to be FDCA followed by HMFG, which together accounted for up to 90% of the HMF dose in the healthy subjects and cancer patient. The metabolism of the cancer sufferer appeared to be slower than the others but the metabolites were the same.

In all cases, no HMFA was detected, even though this has been described as the major metabolite in previous reports. The researchers suggested that this is due to the rapid metabolism of HMF to HMFA then quickly on to FDCA, occurring within two hours before the first urine sample was taken. The absence of HMF in the urine and the observation of oxidation as the main metabolic pathway are consistent with this conclusion.

Another absentee was the sulphoxy metabolite SMF, which was not found in any of the subjects. Although the researchers did not really expect to see SMF, as it has never been reported in human studies, its confirmed absence is another step in assuring the safety of medicines containing HMF.

One prominent peak appeared in the chromatogram which could not be identified. It has been reported by another research group to be an oxidised form of HMFG, N-carboxyfuroylglycine and its confirmation will be the subject of future work by Schmid using LC/MS to pin down its structure.  

This is the first published procedure for measuring this drug and its real and potential metabolites in one experiment. It has ruled out the appearance of one potentially toxic metabolite and has assured the safety of medications containing HMF, like Sanopal and Karal.

Related Links

Journal of Separation Science 2013, 36, 670-676: "Determination of metabolites of 5-hydroxymethylfurfural in human urine after oral application"

Article by Steve Down

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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