Reaction mass of 1-O-α-D-glucopyranosyl-D-mannitol and 6-O-α-D-glucopyranosyl-D-glucitol

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

Metabolism of Hydrogenated Palatinose, an Equimolar Mixture of α-D-Glucopyranosido-1,6-sorbitol and α-D-Glucopyranosido-1,6-mannitol

Author:

Grupp, U. and Siebert, G.

Year:

1978

Bibliographic source:

Res. Exp. Med. (Berl.), 173: 261-278

Materials and methods

Objective of study:

metabolism

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Female rats of 180 g were adapted to 34.5% test item in the diet during 24 days. On the day of the experiment, 5 g food containing 1.7 g test item were fed to the fasted animals, and 20 animals sacrified 0.5-1 h after start of feeding, 20 animals 2-3 h later, 5 animals after 4.5 h and 9 animals after 6 h. The contents of stomach, small intestine, caecum and large intestine were collected under methanol, and the combined samples of each time period and anatomical location analysed by gas chromatography.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Reaction mass of 1-O-α-D-glucopyranosyl-D-mannitol and 6-O-α-D-glucopyranosyl-D-glucitol

EC Number:

908-700-6

Cas Number:

64519-82-0

Molecular formula:

6-O-alpha-D-Glucopyranosyl-D-sorbitol: C12H24O11 1-O-alpha-D-Glucopyranosyl-D-mannitol: C12H24O11

IUPAC Name:

Reaction mass of 1-O-α-D-glucopyranosyl-D-mannitol and 6-O-α-D-glucopyranosyl-D-glucitol

Radiolabelling:

no

Test animals

Species:

rat

Strain:

other: SIV-50

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Ivanovas, Kisslegg, Germany
- Weight at study initiation: 180 g
- Housing: individually in wire cages
- Diet: Altromin (Altrogge, Lage, Geramny), offered in limited amounts
- Water: tap water from bottles, ad libitum
- Acclimation period: not specified

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 1
- Humidity (%): 55

Administration / exposure

Route of administration:

oral: feed

Vehicle:

not specified

Details on exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): not specified
- Experimental diets were based on casein-starch as follows: 20% casein, 0.24% vitamin mixture, 4% salt mixture, 5% hydrogenated vegetable oil, 2% cellulose, 69% corn starch. Additions of test item, GPS or GPM respectivcly were made by exchanging 50% of starch or saccharose with the corresponding disaccharidc alcohols, giving 34.5% of each component. At the start of feeding experiments, however, the initial diet contained only 10% of the disaccharide alcohols, which was raised to 20%, 30% and finally 34.5% within a few days each, in order to avoid diarrhoea.

Duration and frequency of treatment / exposure:

Following 24 days of adaption to increasing amounts of test item in the diet, animals were fasted and subsequently dosed once with 1.7 g/animal in 5 g of diet

Doses / concentrations

Dose / conc.:

1.7 other: g/animal

Remarks:

in 5 g synthetic diet

No. of animals per sex per dose / concentration:

5 to 20 animals per sampling time point

Control animals:

no

Details on dosing and sampling:

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: intestinal contents (stomach, small intestine, caecum, large intestine)
- Time and frequency of sampling: 0.5-1 h after start of feeding (20 animals), 2-3 h after feeding (20 animals), 4.5 h after feeding (5 animals), 6 h after feeding (9 animals)
- From how many animals: see above, pooled samples were analysed
- Method type for identification: gas chromatography
- Limits of detection and quantification: not specified

Statistics:

All statistical calculations were done with Student's t-test.

Results and discussion

Preliminary studies:

not specified

Main ADME results

Type:

metabolism

Results:

Ingested test item partially arrived unsplit in the caecum and underwent fermentation there; excretions in faeces and urine are neglegible in the rat.

Metabolite characterisation studies

Metabolites identified:

yes

Remarks:

α -D-glucopyranosido-1,6-sorbitol , α-D-glucopyranosido-1,6-mannitol, sorbitol and mannitol

Details on metabolites:

The time course of the fate of test item in the digestive tract is depicted in Table 1. While the stomach is being emptied after a standard dose of 1.7 g in 5 g synthetic diet, progressively more disaccharide alcohols and hexitols are found in small intestine, caecum, and to some extent also in large intestine, as time proceeds. lt follows from these data, that uncleaved disaccharide alcohols appear beyond the small intestine and must have escaped digestion by carbohydrases in the upper part of the digestive tract. α -D-glucopyranosido-1,6-sorbitol (GPS) and α-D-glucopyranosido-1,6-mannitol (GPM) are found in small intestine at 5-14% of the amount in the stomach. Three to six hours after the test meal, per animal 80-105 mg of disaccharide alcohols plus hexitols are found beyond the small intestine. Whereas these compounds may exist in even Iarger amounts in the caecum than in small intestine at intermediate times, a sharp decrease is observed between caecum and large intestine: after, e.g., 4.5 h, 4.8 to 8.3 times higher amounts of all four compounds are recovered from the caecum than from the Iarge intestine. Obviously, the caecum is functioning like a sink for disaccharide alcohols as well as hexitols which points to this part of the gut as the site where substances which have escaped digestion and/or absorption in small intestine, are cleaved and eventually fermented.
Actually, caeca were enlarged, both in tissue and in total. weights, and their content is always a grayish mass with many small gas bubbles, indicating fermentation. From the data of Table 2 it can be concluded that disaccharide alcohols as well as hexitols disappear while passing through the caecum, thus cleavage of glycoside bonds as well as bacterial fermentation obviously proceeds in this organ.

A small portion of disaccharide alcohols is excreted in stool and feces respectively. Data for rat faeces demonstrate that after a few days the test item is excreted just at the level of analytical detectability. In experiments with healthy human volunteers, only neglegible amounts of test item are found in the stool. Accordingly, the test item undergoes practically complete degradation in man and rat during passage through the digestive tract. Whatever amount may have escaped caecal fermentation (see data for large intestine in Table 1) becomes obviously finally degraded in the colon or rectum.

Any other information on results incl. tables

Table 1. Disaccharide alcohols and hexitols in the intestinal tract of rats (mg/animal)

Time period after feeding (h)			GPS	GPM	Sorbitol	Mannitol
0.5 -1		stomach	205	260	6	5
		small intestine	20	35	22	15
		caecum	5	5	8	9
		large intestine	0	0	0	0
2 - 3		stomach	155	170	7	6
		small intestine	23	45	25	1.5
		caecum	5	35	42	40
		large intestine	0	5	6	3
4.5		stomach	80	100	6	3
		small intestine	25	50	22	12
		caecum	24	65	27	25
		large intestine	5	10	5	3
6		stomach	25	30	3	2
		small intestine	20	30	12	10
		caecum	18	70	21	15
		large intestine	5	12	3	2