In our studies on the pharmacokinetics and biodistribution of 1,3-β-glucans administered orally, we observed three peaks in plasma concentration. The first peak occurred half an hour after administration, followed by a rapid decrease. The second peak was observed between 2 and 10 hours later, and the final peak occurred at 34 hours after oral administration of 5mg/kg of β-glucans from Maitake PRO4X. Rice et al. (2005) (9) reported similar findings, indicating plasmatic peaks of water-soluble glucans between 0.5 to 12 hours after oral administration, with sustained presence in serum up to 24 hours and significant biological effects.
Our results suggest that the clearance of 1,3-β-glucans from plasma follows a first-order kinetic model, characterized by rapid clearance starting half an hour after oral administration, followed by a more gradual elimination 10 hours later. Hong et al. (2004) (10) reported that orally administered β-1,3-glucans are transported by macrophages to the spleen, lymph nodes, and bone marrow, which could contribute to the plasma reduction of the compound. We observed that the absorption of the compound exceeded its elimination, resulting in a high volume of distribution (127 ml/g), indicating extensive distribution in tissues with possible accumulation and limited binding to plasma proteins. This suggests that 1,3-β-glucans are predominantly present in their "free" form in circulation, allowing them to diffuse into extravascular compartments, interact with receptors, and trigger biological responses. On the other hand, protein binding may result in reduced biological activity due to inactivation, as reported by Miura et al. (1997) (11).
In our pharmacokinetic studies involving intravenous administration, we observed two peaks in plasma concentration of 1,3-β-glucans. The first peak occurred two hours after administration, followed by a gradual decrease, and the second peak was observed at 10 hours. The clearance of 1,3-β-glucans from plasma also followed a first-order kinetic model, with rapid elimination starting half an hour after intravenous administration and a more gradual elimination at 10 hours. The volume of distribution obtained was higher than that of oral administration (1418.5 mL/g), indicating extensive tissue distribution. Similar to oral administration, we observed limited plasma protein binding, suggesting a significant proportion of the compound remains in its "free" form in circulation.
Our biodistribution studies revealed a higher uptake of 1,3-β-glucans in the gastrointestinal tract, particularly in the stomach and duodenum. Significant uptake was also observed in the colon. This uptake in the stomach may be attributed to the acidic nature of the Maitake glycoprotein extract, allowing a higher percentage of non-ionized molecules to be absorbed. Studies by Vetvicka et al. (2007) (12) in rats demonstrated a higher detection of β-glucans in the stomach and duodenum shortly after administration, which decreased over time.
Intestinal absorption of 1,3-β-glucans involves specialized transporters and multiple mechanisms, including internalization by intestinal epithelial cells, gut-associated lymphoid tissue (GALT) cells, and subsequent transportation by macrophages to the bone marrow and reticuloendothelial system. The fragments of β-glucans are released by macrophages and taken up by other immune cells, leading to various immune responses. The presence of receptors such as Dectin-1 in macrophages and dendritic cells further supports the role of these cells in β-glucan translocation. Additionally, β-glucans can interact with mast cells and potentially inhibit their degranulation, reducing allergic reactions.
Our biodistribution studies also revealed significant uptake of 1,3-β-glucans in the brain, indicating the ability of Maitake glycoprotein extract to cross the blood-brain barrier (BBB). The BBB is a selective barrier that regulates the exchange of molecules between blood and the brain. The presence of Dectin-1 receptors on microglial cells suggests that 1,3-β-glucans may be internalized by these cells and reach the CNS. Additionally, significant uptake was observed in the lungs, suggesting innate recognition of fungi mediated by receptors such as Dectin-1.
Hepatic and renal uptake of 1,3-β-glucans was relatively low compared to other organs involved in metabolism and elimination. This suggests a lower rate of inactivation and excretion, potentially contributing to the prolonged presence of the compound in circulation. Previous studies have reported similar findings, indicating that the liver does not significantly contribute to plasma glucan removal.
Overall, our studies provide insights into the pharmacokinetics and biodistribution of 1,3-β-glucans administered orally and intravenously, highlighting their absorption, distribution, metabolism, and elimination in various organs. These findings contribute to a better understanding of the compound's behavior and potential biological effects.