Metabolism and pharmacokinetics of [14C]-deoxyfructosylserotonin creatinine sulfate administered orally and intravenously to rats and mice.

Deoxyfructosylserotonin (DFS) has been shown in in vitro tests to inhibit L-DOPA-oxidase and also to suppress the multiplication of Mycobacterium leprae. The possible therapeutic use of DFS makes necessary the study of its metabolic fate in animal models. Labelled [14C]-DFS was synthesized by condensation of serotonin and [14C]-glucose and administered per os or intravenously to rats and mice. After oral administration, some of the radioactivity transited through the intestinal tract to be excreted in feces (20-60% of the dose) and some was destroyed in the pH conditions of the intestine and further metabolized by the flora, producing 14CO2 in the expired air (10-40% of the dose). Radioactivity excreted in the urine amounted to 8-15% after 24 h. After intravenous administration, 60-90% of the dose had already been excreted in the urine after 8 h. Feces and CO2 accounted for 5-10% each. In the urine, for both routes of administration, beside DFS, half of the radioactivity corresponded to the glucuronide conjugate, while in the feces all the radioactivity found was unchanged DFS. Whole animal body autoradiography showed the presence of radioactivity in all the organs (1-2% of the dose) mainly resulting from the incorporation of labelled carbon from glucose and CO2. These results, obtained in healthy rats, demonstrate poor intestinal absorption of DFS (10% of the dose) and when it is absorbed, rapid urinary excretion. For its possible therapeutic use as an anti-leprosy drug in humans, derivatives with higher bioavailability must be attained.

[Desoxyfructo-serotonin: its therapeutic effect in the treatment of leprosy]. / La desoxyfructo-serotonine: son effet thérapeutique dans le traitement de la lèpre.

Desoxyfructo-serotonin (DFS) has shown good results in clinical trials of LL patients. After clinical trials in Bamako (Mali) reported in three articles, clinical trials began in India, at Bombay. Acute toxicity tests done in Paris and chronic toxicity tests done in India had shown absence of side effects. This was also confirmed after pre-clinical pharmacology. In vitro tests show that DFS enhances cellular immune response. Receptors for anti-erythrocyte antibody on LL macrophages are demonstrated by erythrocyte rosetting. Infection with M. leprae markedly reduces rosetting. But in the presence of DFS this reduction in rosetting is not observed. Patient's peripheral blood lymphocytes, sensitised with leprosy antigen, show a low level of rosetting with patients' macrophages. DFS greatly enhances the lymphocyte-macrophage interaction. DFS has an important anti-stress activity. Gastric ulcer induced in rats by restraint were reduced by 40% (Mester et al.) and 50% (Das Neves). DFS increased the uptake of serotonin by LL patients platelets. HPLC studies were done to see the level of DFS in the plasma, in the serum and in the urine of LL patients and controls. We are synthetising new lyposoluble derivatives in order to make easier the penetration of DFS and a long time effect.