Cyclooctapentylose

Endpoint summary

Additional information

For this endpoint the read-across approach based on grouping of substances (category approach) was used. .Alpha.-, .beta.- and .gamma.-cyclodextrin are composed of six, seven and eight identical α-D-glucopyranoside units, respectively. The water solubility is between 18,5 and 232 g/L at 25°C with .beta.-cyclodextrin being the least soluble within this group and .gamma.-cyclodextrin having the highest water solubility. Studies have been performed with .gamma.-cyclodextrin and literature data are available for .beta.-cyclodextrin. No study data have been found for .alpha.-cyclodextrin.

It can be concluded that whereas .beta.-cyclodextrin is hydrolyzed in the large intestine by gut microorganism, .gamma.-cyclodextrinis is metabolized to breakdown products by the luminal and/or epithelial enzymes of the gastrointestinal tract. In both cases no intact cyclodextrin is detected in the blood after oral administration. Intravenous dosing of .gamma.-cyclodextrin indicates that the internal enzyme systems are not capable of metabolizing intact cyclodextrin. Whereas .beta.-cyclodextrin is converted mainly to CO2; for .gamma.-cyclodextrin the liver was the primary site of storage of breakdown products (approx. 25% of the oral dose).With a medium solubility of 145 g/L at 25°C and a comparable stability against acidic hydrolysis and human digestive enzymes .alpha.-cyclodextrin can be considered as similar concerning its toxicokinetic properties. A read-across for this endpoint is considered valid and reliable.

 

.beta.-cyclodextrin:

No hydrolyses of the read-across substance .beta.-cyclodextrin will appear in case of an acidic environment in humans. When radioactively spiked material is administered orally to rats in a metabolism study it was metabolized more slowly as starch as indicated by the carbon dioxide exhaled (up to 67% of the radioactivity). Only minor portions were found in the urine and the faeces (up to 5% each). Only minor traces were found in the other organs. (Andersen 1963). When labelled .beta.-Cyclodextrin with a purity of more than 77% is administered to rats the peak blood level of radioactivity is observed 4 to 11 hours after administration. Compared to glucose the respired radioactivity was similar at the low dose group whereas at the higher dose the percentage of respired radioactivity was less. .Beta.-cyclodextrin is not absorbed from the stomach or small intestine to a measurable extend. Hydrolysis occurs in the large intestine by the gut microorganisms up to a level of saturation. Unabsorbed material is excreted in faeces. (Szejtli 1980; Gerlóczy 1981 and 1985).

 

.gamma.-cyclodextrin:

In this study, the absorption, distribution, metabolism and excretion of .gamma.-cyclodextrin were studied. To this extent, rats (4 rats/group/sex) were dosed orally with radiolabelled .gamma.-cyclodextrin using a single oral dose of 1000 mg/kg bw or a single intravenous administration of 600 mg/kg bw. Special attention was paid to the time course of CO2 production after oral administration, occurrence and kinetics of y-cyclodextrin or metabolites in blood after oral and intravenous administration, and the role of the gut flora in the metabolism of .gamma.-cyclodextrin. For the latter purpose, experiments with germfree animals were performed.

After a single oral administration, almost all radioactivity was absorbed from the gastrointestinal tract. .Gamma.-cyclodextrin was predominantly converted to CO2 (ca. 60% of the administered dose). Urine and faeces contained only minor amounts (both ca. 3%). Approximately 25% of the administered dose was not excreted, 48 hour after administration. The tissue distribution of radioactivity after a single oral dose of .gamma.-cyclodextrin shows that the liver was the primary site of storage of breakdown products (5-10% of the radioactive dose). It is very likely that .gamma.-cyclodextrin was metabolized to glucose, which was stored in liver glycogen. The amount present in the liver of germfree rats was much lower than in conventional rats, most likely due to a more direct utilization of glucose. After intravenous administration, the concentration of radioactivity in the liver was much lower than after oral administration. Using this route of administration, .gamma.-cyclodextrin was predominantly excreted unchanged in the urine.

No intact cyclodextrin was detected in the blood after oral administration. It can be concluded that .gamma.-cyclodextrin is metabolized to breakdown products (ring-opened oligodextrins, glucose, low molecular weight sugar metabolites and CO2) by the luminal and/or epithelial enzymes of the gastrointestinal tract before entering the blood circulation. This conclusion is based on the following observations: Using germfree rats, the amount of CO2 produced was ca. 13% higher than produced in rats with a conventional gut flora. This increase is most likely due to a differential kinetic behaviour of the absorbed metabolites for germfree and conventional rats. Intravenous dosing of .gamma.-cyclodextrin resulted only in production of minimal amounts of radiolabelled CO2,most likely derived from metabolism after passive diffusion of .gamma.-cyclodextrin into the intestines via the intestinal water balance. This indicates that the internal enzyme systems, with emphasis on the liver, are not to any major extent capable of metabolizing intact cyclodextrin. The time course of CO2 production after a single oral administration of .gamma.-cyclodextrin indicates processing of .gamma.-cyclodextrin in the proximal part of the small intestines. No detectable amount of .gamma.-cyclodextrin was present in the blood of rats after oral administration. In conclusion, .gamma.-cyclodextrin is metabolized to a large extent by enzymes in the gastro intestinal tract to breakdown products which are almost completely absorbed and subsequently excreted as CO2.