6-deoxy-L-mannose

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Objective of study:

absorption

Qualifier:

no guideline available

Principles of method if other than guideline:

A study of the behaviour of L-Rhamnose after oral administration to white rats was undertaken.

GLP compliance:

no

Species:

rat

Strain:

not specified

Sex:

male

Details on test animals or test system and environmental conditions:

Rats whose weights were 100 to 125 g after a fasting period of 24 hours were used.

Route of administration:

oral: gavage

Vehicle:

not specified

Details on exposure:

Rats were fasted for 24 hours. A known amount of the test substance was introduced by stomach tube.

Duration and frequency of treatment / exposure:

Single oral dose

Dose / conc.:

141 other: mg (up to 775 mg)

No. of animals per sex per dose / concentration:

7-10 males per timepoint
17 rats were used for controls

Details on dosing and sampling:

The test substance was introduced to male rats via stomach tube and after the desired interval of time, the animals were killed with chloroform. The entire gastrointestinal tract was exposed, ligated at each end, and removed. The tract was split open and the contents were washed out with several portions of hot water into a volumetric flask of 100 cc capacity. After cooling, 5 cc of 10% sodium tungstate and a like amount of 0.66 N sulfuric acid were added, the contents of the flask were diluted to the mark with water, and the precipitated proteins were filtered off. The filtrates were used for the determination of the amount of unabsorbed substance. One group of 17 rats served as controls for determining the normal reduction values of the contents of the gastrointestinal tract after a 24 hour fast. Most of the rats used for the determination of the absorption coefficient were used also for glycogen estimations. Therefore, after removal of the gastrointestinal tract from 5 to 10 minutes were needed for the preparation of the tissues for glycogen analysis. The gastrointestinal tracts as removed from the animals were placed in covered beakers and kept in the ice box until all rats for that day had been killed. When this procedure was followed, analysis of the gastrointestinal contents was begun within 1.5 to 2 hours after the death of the rat. In the glycogen determinations, the glucose formed by the hydrolysis of glycogen was estimated and a factor was used for the conversion of glucose into glycogen.

Type:

absorption

Results:

The absorption coefficient decreased with the increased duration of the period of absorption. No significant absorption of the test substance occurred after the 1st hour.

Details on absorption:

The absorption coefficient of the test substance decreased with the increased duration of the period of absorption; i.e., absorption coefficients (mg per 100 g of rat per hour) of 41, 20, and 12 for 1-, 2-, and 3-hour absorption periods, respectively. The absolute amount of test substance absorbed per 100 g of rat was nearly constant in all the periods of absorption regardless of the duration of absorption, 41, 40, and 36 mg, respectively. This suggests that no significant absorption of test substance occurred after the first hour. After oral administration of glucose in mixture with the test substance, glucose was well absorbed from the gastrointestinal canal as when glucose was fed alone. This is believed to indicate that the poor absorption of the test substance is not to be ascribed to any toxic effects of the test substance fed. In phlorhizinized rats, the rate of absorption of the test substance was decreased to about 50% of the normal value. No evidence was obtained that under the experimental conditions, oral administration of the test substance resulted in a deposition of glycogen in the liver or that the test substance was superior to xylose as a precursor of glycogen.

Conclusions:

The absorption coefficient of the test substance decreased with the increased duration of the period of absorption. No significant absorption of the test substance occurred after the first hour.

Executive summary:

The test substance was introduced to male rats via stomach tube and after the desired interval of time, the animals were killed with chloroform. The entire gastrointestinal tract was exposed, ligated at each end, and removed. The tract was split open and the contents were washed out with several portions of hot water into a volumetric flask of 100 cc capacity. After cooling, 5 cc of 10% sodium tungstate and a like amount of 0.66 N sulfuric acid were added, the contents of the flask were diluted to the mark with water, and the precipitated proteins were filtered off. The filtrates were used for the determination of the amount of unabsorbed substance. One group of 17 rats served as controls for determining the normal reduction values of the contents of the gastrointestinal tract after a 24 hour fast. Most of the rats used for the determination of the absorption coefficient were used also for glycogen estimations. Therefore, after removal of the gastrointestinal tract from 5 to 10 minutes were needed for the preparation of the tissues for glycogen analysis. The gastrointestinal tracts as removed from the animals were placed in covered beakers and kept in the ice box until all rats for that day had been killed. When this procedure was followed, analysis of the gastrointestinal contents was begun within 1.5 to 2 hours after the death of the rat. In the glycogen determinations, the glucose formed by the hydrolysis of glycogen was estimated and a factor was used for the conversion of glucose into glycogen. The absorption coefficient of the test substance decreased with the increased duration of the period of absorption; i.e., absorption coefficients (mg per 100 g of rat per hour) of 41, 20, and 12 for 1-, 2-, and 3-hour absorption periods, respectively. The absolute amount of test substance absorbed per 100 g of rat was nearly constant in all the periods of absorption regardless of the duration of absorption, 41, 40, and 36 mg, respectively. This suggests that no significant absorption of test substance occurred after the first hour. After oral administration of glucose in mixture with the test substance, glucose was well absorbed from the gastrointestinal canal as when glucose was fed alone. This is believed to indicate that the poor absorption of the test substance is not to be ascribed to any toxic effects of the test substance fed. In phlorhizinized rats, the rate of absorption of the test substance was decreased to about 50% of the normal value. No evidence was obtained that under the experimental conditions, oral administration of the test substance resulted in a deposition of glycogen in the liver or that the test substance was superior to xylose as a precursor of glycogen.

Additional information

L-Rhamnose (rhamnose) is a naturally occurring sugar which can be classified as a methyl-pentose or 6-deoxy-hexose. L-Rhamnose occurs commonly bound to other sugars as a glycone component of glycosides in many plants. L-Rhamnose does not appear to be a substrate for mammalian glycogenic metabolism, but has been used as a marker for intestinal permeability and renal excretion.

 

In a study to investigate intestinal absorption, male rats were administered 141 to 775 mg test substance via single oral gavage (Silberman and Lewis, 1933). The mean (±1 SD) dose for 35 rats was 3300 (±1400) mg/kg body weight. The percent absorption was 13 (±5)% over 1 to 3 hours after administration. The majority of absorption occurred within 1 hour. Upon co-administration, the absorption of glucose was non significantly altered by the presence of L-rhamnose.

 

In a comparative study of species differences in intestinal permeability, six fasted male heathy human volunteers were given 5 g of L-rhamnose in 200 mL of drinking water (Delahunty and Hollander, 1986). Urine was collected over 6 hours. Percent recovery in urine was 16.3 ± 2.5%. Assuming a 70 kg body weight, the dose equivalent was approximately 71 mg/kg bw. In male rats (n=8, 200-250 g/rat) administered a dose of rhamnose at 444 mg/kg bw (assuming 225 g rat), the mean percent of dose recovered in urine after 8 hours was 2.8 ± 1.5%.

 

Thirteen male human volunteers were given an oral sugar solution containing 1 g test substance (Mooradian et al. 1986). Assuming a body weight of 70 kg, the dose equivalent was approximately 14 mg/kg bw. Excretion in humans was 84.3±18.4 mg/5 hours with a range of 31.5-290 mg/5 hours. The mean percent of dose recovered in urine was 8.4 ±1.8% with a range of 3.2-29%.

 

Seventeen male or female volunteers were given an oral solution containing 1 g test substance, approximately equivalent to 14 mg/kg bw. Urine was collected for 6 hours and the mean recovery of the test substance was 10.1±4.9% (Howden et al. 1991).

 

Excretion of the test substance was examined in human volunteers after intravenous and oral dose administration of L-rhamnose (Bjarnason et al. 1994). After an intravenous administration, the L-rhamnose marker was rapidly excreted in urine (49.6% of the dose in 0-2.5 hours and 71.7% in 0-24 hours). After oral administration, 13.7 ± 4.6% of the dose (1 g/subject assumed equivalent to 14 mg/kg bw) was recovered at 0-10 hours.

 

In summary, L-rhamnose is a plant-derived sugar apparently not subject to mammalian glycogenic metabolism. Rapid uptake and excretion in urine as intact test substance occurs when L-rhamnose was used as a physiological marker of intestinal permeability and renal excretion. In humans, recovery in urine after oral administration accounted 8 to 16% of doses given at dose of 14 or 71 mg/kg body weight.