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Toxicity Effects

CAS Registry Number: 3416-24-8

Selected toxicity information from HSDB, one of the National Library of Medicine's databases. 2.

Names 1

    Human Toxicity Excerpts

    • None found

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    Non-Human Toxicity Excerpts

    • LABORATORY ANIMALS: Acute Exposure: Glucosamine (Glmn), a product of glucose metabolism via the hexosamine pathway, causes insulin resistance in isolated adipocytes by impairing insulin-induced GLUT 4 glucose transporter translocation to the plasma membrane. /It was/ hypothesized that Glmn causes insulin resistance in vivo by a similar mechanism in skeletal muscle. Euglycemic hyperinsulinemic clamps (12 mU/kg/min + 3H-3-glucose) /were performed/ in awake male Sprague-Dawley rats with and without Glmn infusion at rates ranging from 0.1 to 6.5 mg/kg/min. After 4h of euglycemic clamping, hindquarter muscles were quick-frozen and homogenized, and membranes were subfractionated by differential centrifugation and separated on a discontinuous sucrose gradient (25, 30, and 35% sucrose). Membrane proteins were solubilized and immunoblotted for GLUT 4. With Glmn, glucose uptake (GU) was maximally reduced by 33 +/- 1%, P < 0.001. The apparent Glmn dose to reduce maximal GU by 50% was 0.1 mg/kg/min or 1/70th the rate of GU on a molar basis. Control galactosamine and mannosamine infusions had no effect on GU. Relative to baseline, insulin caused a 2.6-fold increase in GLUT 4 in the 25% membrane fraction (f), P < 0.01, and a 40% reduction in the 35%f, P < 0.05, but had no effect on GLUT 4 in the 30% f, P= NS. Addition of Glmn to insulin caused a 41% reduction of GLUT 4 in the 25%f, P < 0.05, a 29% fall in the 30%f, and prevented the reduction of GLUT 4 in the 35% f. The 30%f membranes were subjected to a second separation with a 27 and 30% sucrose gradient. Insulin mobilized GLUT 4 away from the 30%f, P < 0.05, but not the 27% f. In contrast, Glmn reduced GLUT 4 in the 27%f, P < 0.05, but not the 30%f. Thus Glmn appears to alter translocation of an insulin-insensitive GLUT 4 pool. Coinfusion of Glmn did not alter enrichment of the sarcolemmal markers 5'-nucleotidase, Na+/K+ATPase, and phospholemman in either 25, 30, or 35% f. Thus Glmn completely blocked movement of Glut 4 induced by insulin. Glmn is a potent inducer of insulin resistance in vivo by causing (at least in part) a defect intrinsic to GLUT 4 translocation and/or trafficking. These data support a potential role for Glmn to cause glucose-induced insulin resistance (glucose toxicity).[A D Baron et al; J Clin Invest 96 (6): 2792-801 (1995)] **PEER REVIEWED** PubMed Abstract Full text: PMC185989
    • LABORATORY ANIMALS: Acute Exposure: Glucose toxicity and glucosamine-induced insulin resistance have been attributed to products of glucosamine metabolism. In addition, endothelial cell nitric oxide synthase is inhibited by glucosamine. Since insulin has endothelial nitric-oxide-dependent vasodilatory effects in muscle, we hypothesise that glucosamine-induced insulin resistance in muscle in vivo is associated with impaired vascular responses including capillary recruitment. Glucosamine (6.48 mg kg(-1) min(-1) for 3 h) was infused with or without insulin (10 mU kg(-1) min(-1)) into anaesthetised rats under euglycaemic conditions. Glucosamine infusion alone increased blood glucosamine (1.9+/-0.1 mmol/l) and glucose (5.4+/-0.2 to 7.7+/-0.3 mmol/l) (p<0.05) but not insulin. Glucosamine induced both hepatic and muscle insulin resistance as evident from measures of glucose appearance and disposal as well as hind-leg glucose uptake, which was inhibited by approx. 50% (p<0.05). Insulin-mediated increases in femoral arterial blood flow and capillary recruitment were completely blocked by glucosamine. Glucosamine mediates a major impairment of insulin action in muscle vasculature associated with the insulin resistance of muscle. Further studies will be required to assess whether the impaired capillary recruitment contributes to insulin resistance.[Wallis MG et al; Diabetologia 48 (10) :2131-9 (2005)] **PEER REVIEWED** PubMed Abstract
    • LABORATORY ANIMALS: Acute Exposure: We determined the effect of infusion of glucosamine (GlcN), which bypasses the rate limiting reaction in the hexosamine pathway, on insulin-stimulated rates of glucose uptake and glycogen synthesis in vivo in rat tissues varying with respect to their glutamine:fructose-6-phosphate amidotransferase (GFA) activity. Three groups of conscious fasted rats received 6-hr infusions of either saline (BAS), insulin (18 mU/kg x min) and saline (INS), or insulin and GlcN (30 umol/ kg x min, GLCN). [3-(3)H]glucose was infused to trace whole body glucose kinetics and glycogen synthesis, and rates of tissue glucose uptake were determined using a bolus injection of [1-(14)C]2-deoxyglucose at 315 min. GlcN decreased insulin-stimulated glucose uptake (315-360 min) by 49% (P less than 0.001) at the level of the whole body, and by 31-53% (P less than 0.05 or less) in the heart, epididymal fat, submandibular gland and in soleus, abdominis and gastrocnemius muscles. GlcN completely abolished glycogen synthesis in the liver. GlcN decreased insulin-stimulated glucose uptake similarly in the submandibular gland (1.3 + or - 0.2 vs. 2.0 + or - 0.3 nmol/mg protein x min, GLCN vs. INS, P less than 0.05) and gastrocnemius muscle (1.4 + or - 0.3 vs. 3.1 + or - 0.5 nmol/mg protein x min), although the activity of the hexosamine pathway, as judged from basal GFA activity, was 10-fold higher in the submandibular gland (286 + or - 35 pmol/mg protein x min) than in gastrocnemius muscle (27 + or - 3 pmol/mg protein x min, P less than 0.001). These data raise the possibility that overactivity of the hexosamine pathway may contribute to glucose toxicity not only in skeletal muscle but also in other insulin sensitive tissues. They also imply that the magnitude of insulin resistance induced between tissues is determined by factors other than GFA.[Virkamaki A et al; Endocrinology 138 (6): 2501-7 (1997)] **PEER REVIEWED** PubMed Abstract

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    Human Toxicity Values

    • None found

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    Non-Human Toxicity Values

    • None found

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    Absorption, Distribution And Excretion

    • About 90% of glucosamine administered orally as a glucosamine salt get absorbed from the small intestine, and from there it is transported via the portal circulation to the liver. It appears that a significant fraction of the ingested glucosamine is catabolized by first-pass metabolism in the liver. Free glucosamine is not detected in the serum after oral intake, and it si not presently known how much of an ingested dose is taken up in the joints in humans. Some uptake in the articular cartilage is seen in animal studies.[Physicians Desk Reference (PDR) for Nutritional Supplements 1st ed, Medical Economics, Thomson Healthcare; Montvale, NJ (2001) p187.] **PEER REVIEWED**
    • Eighteen subjects with osteoarthritis were given 1,500 mg of commercial glucosamine sulphate after an overnight fast, and serum was then obtained at baseline and every 15-30 minutes over 3 hours, and additionally, from two subjects at 5 and 8 hours. Urine samples were collected at baseline and 3 hours after ingestion from three subjects. Baseline glucosamine was below the detection limit of 0.5 umol/L for all subjects, but after ingestion, glucosamine was detected in 17/18 subjects, beginning to rise at 30-45 minutes to a maximum at 90-180 minutes, with a range of 1.9-11.5 umol/L (0.34-2 ug/ml).[Bittee BA et al; Ann Rheum Dis 65 (2): 222-6 (2006)] **PEER REVIEWED** PubMed Abstract Full text: PMC1798018
    • Information on the absorption and serum pharmacokinetics for dietary glucosamine is very limited, and in some case, the available data are contradictory. For example, in one series of studies, (14)C-glucosamine was given orally to rats, dogs, and humans, and in all cases, the radiolabel was described as "efficiently" absorbed, reaching a plasma peak after about 4 hours. A high percentage of the radiolabel (about 35%) was excreted in the urine, and a similar amount was last in expired air. On the other hand, the laboratory that conducted this experiment was unable to detect chemical amounts of glucosamine in human serum after a single oral dose at 100 mg/kg (five times the clinical dose) using a chromatographic assay with a limit of detection of about 14 uM. This suggests that the bioavailable glucosamine in human serum after the normal recommended dosage (20 mg/kg) is well below 10 uM.[Coates, P.M., Blackman, M.R., Cragg, G.M., Levine, M., Moss, J., White, J.D. (Ed), Encyclopedia of Dietary Supplements. Marcel Dekker, New York, NY, p. 280 (2005)] **PEER REVIEWED**
    • The pharmacokinetics of glucosamine sulfate was investigated in 6 healthy male volunteers (2 per administration route) using (14)C uniformly labelled glucosamine sulfate and administering it in single dose by intravenous (i.v.), intramuscular (i.m.) or oral route. The results show that after i.v. administration the radioactivity due to glucosamine appears in plasma and is rapidly eliminated, with an initial t1/2 of 0.28 hr. 1-2 hr after administration the radioactivity due to glucosamine disappears almost completely and is replaced by a radioactivity originating from plasma proteins, in which glucosamine or its metabolites are incorporated. This radioactivity reaches a peak after 8-10 hr and then declines with a t1/2 of 70 hr. About 28% of the administered radioactivity is recovered in the urine of the 120 hr following the administration and less than 1% is recovered in the feces. After i.m. administration similar pharmacokinetic patterns are observed. After oral administration a proportion close to 90% of glucosamine sulfate is absorbed. Free glucosamine is not detectable in plasma. The radioactivity incorporated in the plasma proteins follows pharmacokinetic patterns which are similar to those after i.v. or i.m. administration, but its concentration in plasma is about 5 times smaller than that after parenteral administration. The AUC after oral administration is 26% of that after i.v., or i.m. administration. The smaller plasma levels of radioactivity after oral administration are probably due to a first pass effect in the liver which metabolizes a notable proportion of glucosamine into smaller molecules and ultimately to CO2, water and urea.[Setnikar I et al; Arzneimittelforschung 43 (10): 1109-13 (1993)] **PEER REVIEWED** PubMed Abstract
    • The purpose of this study was to determine if glucosamine (GL) hydrochloride (FCHG49) and low molecular weight (LMW) chondroitin sulfate (CS) (TRH122) are absorbed after oral administration to horses. The bioavailability of LMWCS was evaluated by quantifying the total disaccharides found in the plasma following chondroitinase ABC digestion. Two separate studies were conducted. In study 1, ten adult horses received the following four treatments in a randomized crossover fashion: (1) i.v. LMWCS (3 g of 8 kDa), (2) p.o. LMWCS (3 g of 8 kDa), (3) i.v. LMWCS (3 g of 16.9 kDa) and (4) p.o. LMWCS (3 g of 16.9 kDa). Each group received 9 g GL with LMWCS. In a second study, each horse (n=2) was randomly assigned to receive either i.v. administration of GL HCl (9 g) or p.o. administration of GL HCl (125 mg/kg). Blood samples were collected, assayed and pharmacokinetic parameters were determined. GL was absorbed after oral dosing with a mean C(max) of 10.6 (6.9) ug/ml and a mean T(max) of 2.0 (0.7) hr. The extent of absorption of LMWCS after dosing with both the 8.0 and 16.9 kDa provides evidence that LMWCS is absorbed orally. C(max) and AUC were higher (p<0.05) for the 16.9 kDa material compared with 8.0 kDa. However, the 16.9 kDa bioavailability was less than 8.0 kDa, but this difference was not significant. This study provides the first report of the bioavailability of orally administered GL and LMWCS in the horse.[Du J et al; Biopharm Drug Dispos 25 (3): 109-16 (2004)] **PEER REVIEWED** PubMed Abstract
    • The purpose of this study was to determine the oral bioavailability and pharmacokinetics of a glucosamine and the disaccharides of chondroitin sulfate after single and multiple-dosing of a glucosamine/chondroitin sulfate combination (Cosamin, Cosequin). Male beagle dogs (n = 8, 12 kg) received the following treatments: (1) IV glucosamine (500 mg)/chondroitin sulfate (400 mg), (2) p.o. glucosamine (1500 mg)/chondroitin sulfate (1200 mg), (3) p.o. glucosamine (2000 mg)/chondroitin sulfate (1600 mg), (4) p.o. glucosamine (1500 mg)/chondroitin sulfate (1200 mg) QD for days 1-7 and p.o. glucosamine (3000 mg)/chondroitin sulfate (2400 mg) from days 8 to 14. Blood samples were collected over 24 hr and glucosamine and the disaccharides of chondroitin sulfate were determined. Pharmacokinetic analysis was performed on glucosamine and total chondroitin sulfate disaccharides and parameters were compared across treatments using ANOVA with post hoc analysis. After the IV administration, glucosamine declined rapidly in a bi-exponential fashion with a mean (+ or - S.D.) elimination t(1/2) of 0.52 (0.25) hr. Glucosamine absorption was relatively fast (C(max) = 8.95 ug/ml, and T(max) 1.5 h after 1500 mg dose) and the mean bioavailability of glucosamine after single dosing was approximately 12%. The extent of absorption of chondroitin sulfate as indicated by the mean C(max) (21.5 ug/ml) and mean AUC (187 ug/ml hr) of total disaccharides after dosing (1600 mg) provides evidence that chondroitin sulfate is absorbed orally. The bioavailability of chondroitin sulfate ranged from 4.8 to 5.0% after single dosing and 200-278% upon multiple dosing. The results of this study show that both glucosamine and chondroitin sulfate (measured as total disaccharides) are bioavailable after oral dosing. In addition, the low molecular weight chondroitin sulfate used in this study displays significant accumulation upon multiple dosing.[Adebowale A et al; Biopharm Drug Dispos 23 (6): 217-25 (2002)] **PEER REVIEWED** PubMed Abstract
    • Twelve healthy volunteers received three consecutive once-daily oral administrations of glucosamine sulfate soluble powder at the doses of 750, 1,500, and 3,000 mg, in an open, randomised, cross-over fashion. Glucosamine was determined in plasma collected up to 48 hr after the last dose. ... Endogenous plasma levels of glucosamine were detected (10.4-204 ng/ml, with low intra-subject variability). Glucosamine was rapidly absorbed after oral administration and its pharmacokinetics were linear in the dose range 750-1,500 mg, but not at 3,000 mg, where the plasma concentration-time profiles were less than expected based on dose-proportionality. Plasma levels increased over 30-folds from baseline and peaked at about 10 microM with the standard 1,500 mg once-daily dosage. Glucosamine distributed to extravascular compartments and its plasma concentrations were still above baseline up to the last collection time.[Persiani S et al; Osteoarthritis Cartilage 13 (12): 1041-9 (2005)] **PEER REVIEWED** PubMed Abstract

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    Metabolism/Metabolites

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    Tsca Test Submissions

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    Footnotes

    1 Source: the NTP's CEBS database.

    2 Source: the National Library of Medicine's Hazardous Substance Database, 02/28/2017.

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