Anti-inflammatory assays on the carrageenin-induced edema and scald-induced hyperalgesia in the hindpaw of rats were studied on polysaccharides obtained from the fruit bodies of various fungi (polysaccharide AC, BC: Tremella fuciformis;MEA, MHA, MCW-A, MCW-N: Auricularia auricula-judae; T-2-HN: Dictophora indusiata;G-A: Ganoderma japonicum). The purified polysaccharides MHA, MCW-A, G-A and T-2-HN exhibited a significant inhibitory effect on carrageenin edema. Among these polysaccharides, T-2-HN (partially O-acetylated alpha-D-mannan) also showed the marked inhibitory effect on scald hyperalgesia. We have found that T-2-HN has more potent anti-inflammatory activity than phenylbutazone in the above two inflammatory models. Since the purified polysaccharide is free from protein and lipid, it is clear that anti-inflammatory effect arises from the polysaccharide itself. The polysaccharides (T-2-HN, locust bean gun, xanthan gum) had little effect on the metabolism of arachidonic acid in canine platelets. The mechanism of the anti-inflammatory activity of the polysaccharide remains obscure.

L‐2‐14C‐3‐methoxy, 4‐hydroxyphenylalanine (L‐14C‐O‐methyldopa) has a biological half‐life of approximately 15 hours in human blood. 3‐Methoxy, 4‐hydroxyphenyllactic acid, homovanillic acid, and 3,4‐dihydroxyphenylacetic acid are metabolites found in the blood. The urinary excretion of radioactivity is slow and only a small proportion of excreted radioactivity represents unchanged O‐methyldopa. The same metabolites are found as in the blood as weU as small amounts of dopa, dopamine, and 3‐methoxytyramine. It is concluded that in man part of the L‐O‐methyldopa undergoes demethylation to dopa, which is further metabolized to dopamine and phenolcarboxylic acids.

Summary: Capecitabine, a new orally available fluorpyrimidine carbamate, is converted to 5-fluorouracil (5-FU) by three sequential reactions involving the enzymes carboxylesterase, cytidine (Cyd) deaminase, and pyrimidine nucleoside phosphorylase (PyNPase). In the present study the plasma level profiles of capecitabine and its metabolites were investigated after single and repeated oral administration to monkeys and mice. The activities of the three enzymes were also determined in several tissues of humans, monkeys, mice, and rats.
Capecitabine was absorbed rapidly and converted to 5-FU in both monkeys and mice after a single oral dosing. The concentration of the intact drug and 5'-deoxy-5-fluorocytidine (5'-DFCR), 5'-deoxy-5-fluorouridine (5'-DFUR), and 5-FU were declined rapidly, as reflected by short half-lives of less than 1 hour in monkeys and 1-4 hours in mice. The AUCs of 5-FU were much lower than those of the intact drug and other metabolites, approximately 10 to 50-fold lower than that for 5'-DFUR expressed on a molar ba sis. In monkeys, the AUC and C_max for capecitabine and its metabolites were dose related, and the AUC ra tio for 5-FU to 5'-DFUR was independent of the dose. 5'-DFUR and the intact drug were prevalent in the plasma, and the 5'-DFCR level was slightly lower. In the monkey plasma, α-fluoro-β-alanine, a catabolite of 5-FU, was one of the main metabolites and showed relatively longer half-lives (5-7 hours). In mice, 5'-DFCR and the intact drug predominated in the plasma, and 5'-DFUR levels were lower than those.
The AUCs of capecitabine, 5'-DFCR, and 5'-DFUR were dose related and similar in both genders during repeated daily oral dosing for 5 weeks in monkeys and mice. These values were not affected by repeated ad ministration.
The unique distribution of three 5-FU generating enzymes was found with interspecies deference. In hu mans, carboxylesterase was almost predominantly located in the liver. The monkey showed patterns of the enzyme activities that were the most similar to those in humans. In mice, the distribution patterns of carbox ylesterase and Cyd deaminase were different from those in humans; however, mice have all three enzyme ac tivities needed to generate 5-FU. On the contrary, in rats, extremely low Cyd deaminase activity was ob served.
The plasma level profiles of capecitabine and its metabolites were consistent with the observed activities of these enzymes in each species. Therefore, it seems that the monkey is the most suitable animal to use for predicting pharmacokinetics and safety of capecitabine in humans.

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