Rapid and complete urinary elimination of [14C]-5-hydroxymethyl-2-furaldehyde administered orally or intravenously to rats.

5-Hydroxymethyl-2-furaldehyde (HMF), is a major product of sugar degradation found in food and solutions used in parenteral nutrition. Labeled [14C]HMF was synthesized by dehydration of [14C]fructose on ion-exchange resin and administered per os (po) and intravenously (iv) to rats. Metabolic balance of radioactivity demonstrated that HMF or its metabolites are rapidly eliminated in the urine with a recovery of 95-100% after 24 h. Literature reported, in some cases, 50% retention in the body. HMF was completely converted to two metabolites, which have been identified by nuclear magnetic resonance (NMR) and mass spectroscopy (MS) as 5-hydroxymethyl-2-furoic acid and N-(5-hydroxymethyl-2-furoyl)glycine. Administration of high doses of HMF showed a similar rapid elimination, but a proportional reduction of the amount of the glycine conjugate produced. Whole-animal-body autoradiography confirm that shortly after administration radioactive material was present in the liver but was mostly in the kidney and the bladder. The only significant difference between po and iv administration was the presence of a higher level of radioactive material in the brain of iv-treated rats.

Placental transfer of the major caffeine metabolite in the rat using 6-amino-5[N-formylmethylamino]1,3[Me-14C]-dimethyluracil administered orally or intravenously to the pregnant rat.

6-Amino-5[N-formylmethylamino]1,3[Me-14C]dimethyluracil (1,3,7-DAU), the most important caffeine metabolite in the rat and a minor one in man was synthesized and administered p.o. or i.v. to pregnant rats. This study demonstrates the distribution of this metabolite in the animal and its transfer to the embryos and the fetus. The fetus was shown to be protected by a placental barrier which leads to a lower fetal tissue exposure 1 h after the administration, the equilibrium between fetus and pregnant rat being reached 4-5 h later. Future studies testing the fetotoxicity of this metabolite compared with caffeine must take into consideration that only about half of the oral dose is absorbed. In addition, similar fetal tissue exposure must be obtained when this metabolite is given orally or is produced from caffeine.

Urinary metabolites of caffeine in young dogs.

Urinary elimination of [1-methyl-14C]caffeine was investigated in young dogs. Mongrel dogs aged 2 days, 1 week, and 5 weeks received single doses of caffeine (50 mg/kg) through an orogastric tube. Eight dogs, each studied once, were involved. At identical times after the dose the ratio of urinary caffeine metabolites to unchanged caffeine was greatest in the 5-week-old and smallest in the 2-day-old puppy; cumulative ratios at (or very close to) the plateau of urinary excretion varied between 8.7 and 17.8 in the 5-week-old, 3.6 and 3.8 in the 1-week-old, and 2.2 and 2.4 in the 2-day-old dogs. The time needed to reach the plateau of the cumulative excretion of radioactivity in the urine decreased with age. Initially only caffeine was detected in the urine of the 2-day-old and 1-week-old dogs; the first quantitatively important metabolites were trimethyluric acid and 6-amino-5-(N-methylformylamino)-1,3 dimethyluracil (also known as 1,3,7-trimethyldihydrouric acid) in the 2-day-old, and the uracil derivative and theophylline in the 1-week-old and the 5-week-old puppies. The percentage of demethylated uric acid metabolites and uracil derivatives increased progressively with increasing age; this indicates increased demethylation, oxidation to uric acids and hydrolysis of the imidazole ring of caffeine with increasing age. These results are consistent with the previously reported slow plasma elimination of caffeine in the newborn and confirm the limited capacity of the young (as compared to the adult) mammal to metabolize caffeine.