Synovial fluid levels and serum pharmacokinetics in a large animal model following treatment with oral glucosamine at clinically relevant doses

Abstract

Objective. To examine the concentration of glucosamine in the synovial fluid and its pharmacokinetics in serum in a large animal model following dosing with glucosamine HCl at clinically relevant levels.Methods. Eight adult female horses were studied. After an overnight fast, glucosamine HCl (20 mg/kg of body weight) was administered by either nasogastric (NG) intubation or intravenous (IV) injection. Blood samples were collected before dosing and at 5, 15, 30, 60, 120, 180, 240, 360, 480, and 720 minutes after dosing. Synovial fluid samples were collected from the radiocarpal joints 48 hours before dosing and at 1 and 12 hours after dosing. Glucosamine was assayed by fluorophoreassisted carbohydrate electrophoresis.Results. The maximum concentration of glucosamine in serum reached ϳ300 M (ϳ50 g/ml) following IV dosing and ϳ6 M (ϳ1 g/ml) following NG dosing. Synovial fluid concentrations reached 9-15 M with IV dosing and 0.3-0.7 M with NG dosing, and remained elevated (range 0.1-0.7 M) in most animals even at 12 hours after dosing. Following NG dosing, the median serum maximal concentration of 6.1 M (range 4.38-7.58) was attained between 30 minutes and 4 hours postdose. The mean apparent volume of distribution was 15.4 liters/kg, the mean bioavailability was 5.9%, and the mean elimination half-life was 2.82 hours.Conclusion. Clinically relevant dosing of glucosamine HCl in this large monogastric animal model results in serum and synovial fluid concentrations that are at least 500-fold lower than those reported to modify chondrocyte anabolic and catabolic activities in tissue and cell culture experiments. We conclude that the apparent therapeutic benefit of dietary glucosamine on pain and joint space width in humans and animals may be secondary to its effects on nonarticular tissues, such as the intestinal lining, liver, or kidney, since these may be exposed to much high levels of glucosamine following ingestion.Glucosamine is now widely taken in the US as a dietary supplement (recommended dosage 20 mg/kg/ day) to relieve the discomfort of osteoarthritis (OA)-related joint pain. In Europe, a patented formulation of glucosamine (glucosamine sulfate) is a prescription drug, which is also widely reported to achieve cartilageprotective effects in knee OA (1,2). A quality assessment and meta-analysis of 6 placebo-controlled clinical trials using both glucosamine HCl (2 studies) and glucosamine sulfate (4 studies) concluded that some degree of efficacy appears probable in treating symptoms of knee OA (3). More recently, 2 meta-analyses of a large number of randomized control trials with glucosamine sulfate consistently concluded that the drug is both safe and effective for the treatment of symptomatic OA (4,5).

A preliminary study of the effects of glucosamine sulphate and chondroitin sulphate on surgically treated and untreated focal cartilage damage

“…This may explain previous observations by Laverty et al that show only ~10% increase of glucosamine concentration in synovial joint fluid was found following intravenous (IV) or nasogastric (NG) dosing as compared to serum concentrations (Meulyzer et al, 2008). This bioavailability was deemed to be insufficient to cause any improvement in cellular expressions or metabolic activity as demonstrated by others (Laverty et al, 2005;Meulyzer et al, 2008). For in vivo effects of glucosamine on chondrocytes to be significant, it has been demonstrated that the monosaccharide component of GS would have to "accumulate" in cartilage to levels at least 500 times higher than those present in the synovial fluid of patients receiving therapeutic dosages (Laverty et al, 2005;Meulyzer et al, 2008).…”

“…past, the roles of these supplements have been queried, particularly in relation to whether direct metabolism can, in effect, aid the increase in production of cartilage proteoglycan sub-units (Laverty et al, 2005). Furthermore, it is also unclear how oral GS and CS reach the defective or repaired sites considering that cartilage itself is avascular (O'Driscoll, 1998;Bentley et al, 2003;Piasecki et al, 2003;Shelbourne et al, 2003).…”

“…Furthermore, it is also unclear how oral GS and CS reach the defective or repaired sites considering that cartilage itself is avascular (O'Driscoll, 1998;Bentley et al, 2003;Piasecki et al, 2003;Shelbourne et al, 2003). Although both drugs claim to possess chondroprotective properties, only GS has been widely described and studied in great detail (Noack et al, 1994;Matheson and Perry, 2003;Richy et al, 2003;Laverty et al, 2005). GS is an amino monosaccharide precursor that is incorporated, either directly or after conversion to galactosamine, into the disaccharide unit of glycosaminoglycans (GAGs) located in proteoglycans (PGs) of cartilage matrix ( Mroz and Silbert, 2004).…”

“…This bioavailability was deemed to be insufficient to cause any improvement in cellular expressions or metabolic activity as demonstrated by others (Laverty et al, 2005;Meulyzer et al, 2008). For in vivo effects of glucosamine on chondrocytes to be significant, it has been demonstrated that the monosaccharide component of GS would have to "accumulate" in cartilage to levels at least 500 times higher than those present in the synovial fluid of patients receiving therapeutic dosages (Laverty et al, 2005;Meulyzer et al, 2008). This condition is therefore unlikely to occur even in patients exposed to prolonged use of GS (Reginster et al, 2001).…”

Disc size markedly influences concentration profiles of intravenously administered solutes in the intervertebral disc: a computational study on glucosamine as a model solute

“…Pharmacokinetics of various solutes have been examined in a wide range of species from animals as large as horses [1,2] to sheep [3,4], dogs [5,6], rabbits [7][8][9] and finally to animals as small as rats and mice [10,11]. Apart from inherent inter-and intra-species differences in cell type, tissue composition and mechanical properties, there is a huge difference between the disc sizes among these species.…”