D-Glucosamine

Crystals, mp 88 °C; specific optical rotation +100 °Changing to +47.5 deg after 30 minutes in water at 20 °C /alpha form/

Needles from methanol, dec 110 °C, specific optical rotation +28 °Changing to +47.5 deg after 30 minutes in water at 20 °C; very soluble in water, soluble in about 38 parts boiling methanol; sparingly soluble in cold methanol or ethanol; practically insoluble in ether, chloroform /beta form/

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 10(SRC), determined from a structure estimation method(2), indicates that glucosamine is expected to have very high mobility in soil(SRC). The pKa of glucosamine is 7.58(3), indicating that this compound will partially exist in cation form in the environment and cations generally absorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization of the neutral form of glucosamine from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 7.7X10-16 atm-cu m/mole(SRC), using a fragment constant estimation method(5). Volatilization of the cation from moist soil surfaces will not occur as ionic species do not volatilize. Glucosamine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 9.0X10-8 mm Hg(SRC), determined from a fragment constant method(6). Glucosamine is expected to biodegrade fairly rapidly in aerobic soil environments based on a grab sample study using two different soils where 36 and 56% mineralization and 65 and 70% mineralization were reported after 1 and 8 weeks, respectively(7).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 10(SRC), determined from a structure estimation method(2), indicates that glucosamine is not expected to adsorb to suspended solids and sediment(SRC). However, glucosamine will exist partially in the cation form at pH values of 5 to 9 based on a pKa of 7.58(5) and cations generally adsorb more strongly to organic carbon and clay than their neutral counterparts(6). Volatilization from water surfaces is not expected(3) for the neutral species based upon an estimated Henry's Law constant of 7.7X10-16 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). Volatilization of the cation from water surfaces is not expected to occur as ionic species do not volatilize. According to a classification scheme(7), an estimated BCF of 3(SRC), from an estimated log Kow of -4.2(8) and a regression-derived equation(9), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Glucosamine is expected to biodegrade fairly rapidly in aerobic water based on a soil grab sample study using two different soils where 36 and 56% mineralization and 65 and 70% mineralization were reported after 1 and 8 weeks, respectively(10).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), glucosamine, which has an estimated vapor pressure of 9.0X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase glucosamine may be removed from the air by wet or dry deposition(SRC). Glucosamine does not contain a chromophore that absorbs at wavelengths >290 nm and therefore is not expected to be susceptible to direct photolysis by sunlight(3).

The Expert Panel for Cosmetic Ingredient Safety concluded that Glucosamine is safe in cosmetics in the present practices of use and concentration described in this safety assessment when formulated to be non-irritating.

Safe for use in cosmetics, with qualifications

Using a structure estimation method based on molecular connectivity indices(1), the Koc of glucosamine can be estimated to be 10(SRC). According to a classification scheme(2), this estimated Koc value suggests that glucosamine is expected to have very high mobility in soil. The pKa of glucosamine is 7.58(3), indicating that this compound will partially exist in cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). The amino sugar units in glucosamine may link, through the action of phenolase enzymes, to soil humic polymers(5).

AEROBIC: The biodegradation of 14-C radiolabeled glucosamine was measured in an acidic Steinbeck loam (pH 5.0, organic carbon 1.48%, sand:silt:clay ratio of 45:36:19%) and a neutral Greenfield sandy loam (pH 7.0, organic carbon 1.02%, sand:silt:clay ratio of 61:26:13%). The percentage of applied activity evolved as CO2 after 1, 8, and 12 weeks was 36, 65, and 67%, respectively, in the Steinbeck soil and 56, 70, and 72% in the Greenfield soil, respectively(1). At 12 weeks, 17.6 and 12.5% of the residual glucosamine in the Steinbeck and Greenfield soils, respectively, was present in the biomass(1). Glucosamine hydrochloride had a calculated mineralization turnover time of 303.4 hours in aquifer solid samples obtained from an aerobic pristine aquifer in Lula, OK(2). These data suggest that glucosamine is expected to degrade fairly rapidly in the environment.

SEDIMENT: A Fanning Island (Central Pacific Ocean) lagoon carbonate mud sediment contained glucosamine at concentrations of 1.41, 1.04, 0.32, 0.19, 0.17, 0.24, and 0.20 umol/g in grain size fractions of <2, 2-6, 6-10, 10-20, 20-40, 63-125, 125-250 microns, respectively(1).

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

GLUCOSAMINE

DILI Positive

Topical

DOI:10.1016/j.drudis.2019.09.022

An estimated BCF of 3 was calculated in fish for glucosamine (SRC), using an estimated log Kow of -4.2(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

Glucosamine has a pKa of 7.58(4) and thus will exist partially as a cation in the environment. Volatilization of the cation from moist soil and water surfaces is not expected because ionic compounds do not volatilize. The Henry's Law constant for the neutral species of glucosamine is estimated as 7.7X10-16 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that glucosamine is expected to be essentially nonvolatile from water surfaces(2). Glucosamine's Henry's Law constant indicates that volatilization of the neutral species from moist soil surfaces will not occur(SRC). Glucosamine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 9.0X10-8 mm Hg(SRC), determined from a fragment constant method(3).

/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).

/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.

/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.

In a pharmacokinetic study, glucosamine was 88.7% absorption by the gastrointestinal tract. Absolute oral bioavailability was 44%, likely due to the hepatic first-pass effect. In a pharmacokinetic study of 12 healthy adults receiving oral crystalline glucosamine, plasma levels increased up to 30 times the baseline levels and Cmax was 10 microM with a 1,500 mg once-daily dose. Tmax was about 3 hours. AUC was 20,216 ± 5021 after a 15,000 mg dose.

Fecal excretion of glucosamine in a pharmacokinetic study was 11.3% within 120 hours after administration. Urinary elimination was found to be 1.19% within the first 8 hours post-administration.

Results of a pharmacokinetic study of 12 healthy volunteers receiving three daily consecutive oral administrations of glucosamine sulfate soluble powder demonstrated glucosamine distribution to extravascular compartments. Human pharmacokinetic data for glucosamine is limited in the literature, however, a large animal model study of horses revealed a mean apparent volume of distribution of 15.4 L/kg. Concentrations of glucosamine ranged from 9-15 microM after an intravenous dose, and 0.3-0.7 microM after nasogastric dosing. These concentrations remained in the range of 0.1-0.7 microM in the majority of horses 12 hours after dosing, suggesting effectiveness of a once-daily dose. In rats and dogs, radioactivity from a C-14 labeled dose of glucosamine is detected in the liver, kidneys, articular cartilage, and other areas.

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.

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.

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.