| Polysaccharide peptide (PSP) is a protein-bound polysaccharide isolated from Coriolus versicolor (strain COV-1), which has been widely used in China as an adjuvant to cancer therapy and as a health product in Hong Kong.; The present study investigated the effects of PSP on the pharmacokinetics of cyclophosphamide, an anti-cancer drug, and antipyrine, a model compound solely dependent on hepatic metabolism for its clearance. PSP (1 mg/ml) decreased the biotransformation of cyclophosphamide by 20% in rat microsomes in vitro. PSP (200 mg/kg, i.p., 3 days) altered the pharmacokinetics of cyclophosphamide in vivo, with the area under curve (AUC) increased by 50%, total clearance (CL) decreased by 33%, and half-life (T 1/2) prolonged by 34%. Further studies with the model compound antipyrine showed that PSP (200 mg/kg, i.p., 3 days) also altered the pharmacokinetic parameters of antipyrine. The AUC of antipyrine was increased by 61%, CL decreased by 33%, and T1/2 prolonged by 55%, suggesting that the cytochrome P450 (CYP)-dependent metabolism of antipyrine was inhibited after subchronic treatment with PSP. Unlike the typical P450 enzyme inhibitor cimetidine, which was effective after a single dose pretreatment, PSP required pretreatment for at least 3 days. This coincides with the observation that PSP dose-dependently (50–400 mg/kg) decreased hepatic P450 contents (32–45%).; The potential analgesic actions of PSP were studied in mice using the hot-plate test and the writhing test. In the hot-plate test, PSP (400 mg/kg, i.p.) decreased the hind paw withdrawal latency by 39% (reduced by morphine), indicating a hyperalgesic rather than an analgesic effect in the mouse. In the acetic acid-induced writhing tests, PSP (400 mg/kg, i.p.) decreased the number of writhes (89%) induced by acetic acid. However, PSP (7.5–100 mg/kg) was observed to induce dose-dependent writhing itself, which can be antagonized by anti-inflammatory drugs such as diclofenac (reduced by 54%) and dexamethasone (59%), and anti-histamine such as diphenhydramine (100%). Further studies with PSP showed that PSP (400 mg/kg, i.p.) activated peritoneal macrophages and mast cells and increased the release of tumour necrosis factor (TNF-α), interleukin 1β (IL-1β), and prostaglandin E 2 (PGE2) by at least 2-fold. Moreover, PSP (0.1 mg/ml) increased histamine release by 110% in vitro. (Abstract shortened by UMI.)... |
