Sucrose, mixed acetate and isobutyrate octaesters

Endpoint summary

Description of key information

Absorbed SAIB in rats, humans and dogs is rapidly eliminated through either intermediary metabolism, the bile or the urine.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

66

Additional information

ADME endpoint summary

 

The subject material, the fully acylated sugar sucrose acetate isobutyrate (SAIB), consists of a mixture represented as approximately 2 mole equivalents of acetate and 6 mole equivalents of isobutyrate per mole equivalent of sucrose. The fate of this material in mammals has been determined by feeding as either a corn oil solution or as an aqueous emulsion to rats, dogs and humans.

 

Fate of ¹⁴C-SAIB in Rats:

 

The radiolabeled material, ¹⁴C-SAIB, was prepared from ¹⁴C(U)-sucrose. In an initial experiment, two rats were dosed with approximately 27 mg/kg bwt of SAIB in corn oil and two additional rats were dosed at 89 and 98 mg/kg bwt of SAIB in corn oil. Elimination of radioactivity was followed for up to 4 days. At the lower dose level, 75 and 82% of the administered dose was absorbed. Lesser amounts, 45 and 50%, were absorbed at the higher dose levels. Elimination of the absorbed dose in the four animals was primarily as ¹⁴CO₂, 50-73%, whereas 22-29% was eliminated in the urine. Slightly larger proportions were eliminated as ¹⁴CO₂at the lower doses and slightly higher proportions were eliminated in the urine at the higher dose levels. Analysis of material eliminated in the feces indicated the presence of either SAIB or highly acylated sucrose.

 

The elimination of ¹⁴C -SAIB has also been studied in rats administered the material as an aqueous emulsion by gastric intubation. The material was administered at dose levels of 5.8 and 11.2 mg/kg bwt and the elimination followed for up to 3 days. A total of 73-77% of the administered SAIB was absorbed from the gastrointestinal tract. Of this, over 73% was converted to ¹⁴CO₂with an additional 14-18% in the urine. The maximum rate of elimination as ¹⁴CO₂occurred within 7 hours after dosing, after which elimination fell off rapidly. A residual 8.3-8.5% of the administered radioactivity was found in the carcasses of animals at necropsy. Paper chromatography of the collected urine indicated that SAIB or highly acylated forms of SAIB were not present and that very little free sucrose was present, but the exact nature of the radioactive species present in urine was not determined. Radioactivity in feces was largely present as SAIB or as highly acylated sucrose species.

 

The elimination of SAIB in the bile of three rats was studied in bile-duct cannulated rats administered single doses of ¹⁴C -SAIB as aqueous emulsions at 19.8, 41.5 or 50.9 mg/kg bwt. Radioactivity levels in blood and bile from rats was followed for up to 20 hours. The first rat did not produce usable results and additional bile from untreated rats was administered to the two remaining treated rats to allow collection of usable amounts of bile. These rats eliminated 2.8 and 4.9% of the dose in the bile within 20 hours. Only very low levels of radioactivity were detected in the blood from treated rats. Paper chromatography of bile collected from rats indicated the possible presence of materials with the chromatographic properties of sucrose or lightly acylated sucrose.

 

Rats were administered ¹⁴C-SAIB in corn oil to determine absorption from the gastrointestinal tract. Two rats were administered ¹⁴C-SAIB in corn oil by intubation at an approximate dose of 100 mg/kg bwt and were killed 3 and 3.5 hours after dose administration. The gastrointestinal tracts were removed from the cardiac valve to the rectum. The intestines were cut into three equal sections. The contents were analyzed quantitatively and by paper chromatography. Chromatograms of the proximal third of the gastrointestinal tract indicated the presence of large amounts of material representing hydrolyzed SAIB. Apparently much of this material represented partially esterified sucrose esters. However, the majority of radioactivity was found in the distal two thirds of the gastrointestinal tract and had chromatographic properties of SAIB or highly acylated sucrose. These results suggest that SAIB is extensively metabolized in the intestines, presumably by deesterification in the presence of lipases or other esterases. Partially deesterified SAIB molecules appear to be largely absorbed from the gastrointestinal tract. The extent to which more highly acylated sucrose molecules are absorbed could not be determined.

 

Fate of ¹⁴C-SAIB in Dogs:

 

Two beagle dogs were administered ¹⁴C -SAIB as an aqueous emulsion at dose levels of 3.0 and 4.8 mg/kg bwt. Elimination of radioactivity in the breath, urine and feces was followed for up to 8 days. Absorption from the gut amounted to only 45 to 53% of the dose in 7 days. Of that absorbed, 48-53% was eliminated as ¹⁴CO₂within 32 hours. A total of 11-14% of the absorbed dose was eliminated in the urine within 7-8 days. Paper chromatography of urine showed that radioactive species were less polar than sucrose, having properties associated with sucrose esters. Chromatographic analysis of fecal extracts (ethanol) indicated that these materials were entirely composed of SAIB or highly acylated sucrose molecules.

 

The bile duct of a single dog was cannulated for the collection of bile. In three separate trials, the dog was administered 4, 4 and 1270 mg/kg bwt of ¹⁴C -SAIB in an aqueous emulsion and levels of radioactivity in blood and bile determined. At the 4 mg/kg bwt dose levels, the dog eliminated over 6% of the radioactivity in the bile within 11 to 15 hours but only 2% at the 1270 mg/kg bwt dose level. Unlike the results obtained with the rat, paper chromatographic analysis of bile from the dog indicated the presence of materials with chromatographic properties of SAIB or highly acylated sucrose with no other significant labeled species.

 

Fate of ¹⁴C-SAIB in Humans:

 

Three male human volunteers were administered ¹⁴C -SAIB as an aqueous emulsion in six experiments at dose levels of 1 mg/kg bwt and in one experiment at 0.2 mg/kg bwt. Breath, urine and feces were monitored for the elimination of radioactivity for up to 25 days. The majority of absorbed material (41 to 66% of the dose) was eliminated as ¹⁴CO₂within 11 days or more and with maximal elimination rates occurring 9-16 hours after dosing. Urinary elimination was rapid and accounted for 14-21% of the administered dose. About 10% of the administered dose was recovered in the feces. Elimination was not influenced by administering unlabeled SAIB to two subjects at a dose of 100 mg/day for 7 days prior to dosing with ¹⁴C -SAIB. Paper chromatographic analysis of ethanol extracts of urine indicated two large peaks with properties intermediate between those of sucrose and SAIB, but no detectable SAIB.

 

Two subjects were fed ¹⁴C (U)-sucrose at a level of 400 mg/kg and the fate of the radioactivity was similarly studied. The subjects metabolized only 41 and 59% of the dose to ¹⁴CO₂within 48 hours and the maximal rate of elimination occurred within 3 hours of dosing. These differences in the rates of elimination of ¹⁴CO₂from ¹⁴C -SAIB and ¹⁴C -sucrose presumably reflect the slower rate at which sucrose from SAIB is presented to the body.

 

Conclusions

 

In vivo metabolism studies in rats and humans with ¹⁴C -SAIB show that it is rapidly metabolized in the gastrointestinal tract, most likely to sucrose and to partially deesterified SAIB. In studies with rats, dogs or humans, rapid elimination of absorbed SAIB from the body was observed, either through intermediary metabolism, the bile or the urine. Dogs differ somewhat from rats and humans in that molecular species suggestive of highly acylated sucrose esters, or SAIB, are eliminated in the urine and bile.