Flutamide is a nonsteroidal antiandrogen used in the treatment of prostatic carcinoma. We have investigated the disposition of flutamide and its two major metabolites in ten urological in-patients without significant liver or renal disease. After oral administration flutamide is absorbed from the gastrointestinal tract with a tmax of about 2 h. Flutamide undergoes extensive first-pass metabolism, and its major metabolites are 2-hydroxyflutamide and the hydrolysis product 3-trifluoromethyl-4-nitroaniline. After the oral administration of a single dose of 250 mg or 500 mg maximum flutamide plasma concentrations of 0.02 and 0.1 micrograms.ml-1 respectively were observed. Maximum plasma concentrations of 2-hydroxyflutamide for the same flutamide doses were 1.3 and 2.4 micrograms.ml-1 (mean of n = 2 or n = 3). Steady-state concentrations of the biologically active metabolite 2-hydroxyflutamide (0.94 +/- 0.23 micrograms.ml-1, mean +/- SD, n = 5) were found at 2-4 days after the administration of 250 mg every 8 h. The area under the plasma concentration time curve for 2-hydroxyflutamide averaged 11.4 (10.6 and 12.1) and 24.3 (21.5-29.4, n = 3) micrograms.ml-1.h for 250 mg and 500 mg flutamide orally. 2-Hydroxyflutamide and 3-trifluoromethyl-4-nitroaniline were eliminated monoexponentially with half-times of 4.3-21.9 and 4.3-17.2 h (n = 5) respectively.
We present two monoclonal antibodies (mab), Mano 4/4 and 486 P3/12, directed against tumor-associated antigens of different subpopulations of transitional cell bladder carcinoma tumors. A detailed description is given concerning their reactivity patterns in an ELISA assay against different cell lines. Using immunohistochemical staining against normal bladder mucosa, mab Mano 4/4 reacts with distinct cells in the basal layer and mab 486 P 3/12 recognizes single cells in the superficial layer. Analysing different transitional-cell carcinomas, mab Mano 4/4 reacts with 17 of 20 and mab 486 P 3/12 with 17 of 19 bladder tumors. It is emphasized that both mabs may add new information in respect to a better characterization of the heterogeneity of bladder carcinoma. A biochemical characterization of the mabs and their corresponding antigens is given. Mab Mano 4/4 is directed against a 28 kD glycoprotein and mab 486 P 3/12 is reacting with a 200 kD glycoprotein belonging to the family of CEA-like proteins.
Human prostate-specific antigen (PSA), a 33 kDa kallikrein-like serine protease, occurring in the prostate, in seminal plasma and in blood, was prepared under nonreducing conditions in an enzymatically active form from seminal plasma by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), followed by fast copper staining, electroelution from gel slices and dialysis against isotonic phosphate-buffered saline (PBS). Enzymatic activity was demonstrated for the first time directly by cleavage of semenogelin, one of the biological substrates of PSA, isolated by the same procedure, i.e. SDS-PAGE and electroelution, but from seminal vesicle fluid. The purified PSA formed SDS-stable complexes with the two major extracellular protease inhibitors in blood, alpha 1-antichymotrypsin (alpha 1-ACH) and alpha 2-macroglobulin (alpha 2-M). PSA isolated under reducing conditions was enzymatically inactive and could not bind to the protease inhibitors alpha 1-ACH and alpha 2-M.
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