2-(allylthio)pyrazine and Body-Weight

The effects of cysteine on the pharmacokinetics of 2-(allylthio)pyrazine (2-AP) were investigated after intravenous administration of the drug (50 mg/kg) to control (Sprague-Dawley) rats (4-week fed on 23% casein diet), and rats with protein-calorie malnutrition (PCM, 4-week fed on 5% casein diet) and PCMC (PCM with 250 mg/kg of oral cysteine, twice daily starting from the fourth week). In rats with PCM, the area under the plasma concentration-time curve from time zero to time infinity (AUC) of 2-AP was significantly smaller than that in control rats. However, in rats with PCMC, the AUC of 2-AP was significantly greater than that in control rats and rats with PCM. This could be due to significantly greater formation of M4 in rats with PCM and significantly smaller formation of M4 in rats with PCMC than that in control rats. In rats with PCMC, some pharmacokinetic parameters of 2-AP restored fully or more than the levels of control rats. For example, in rats with PCMC, the apparent volume of distribution at steady state of 2-AP (7290, 16,600, and 7050 ml/kg for control rats, and rats with PCM and PCMC, respectively), the percentage of dose excreted in 24-h urine as unchanged 2-AP (0.242, 0.727, and 0.130%), and 'the amount' excreted in 24-h urine as M4 (100, 228, and 51%) were comparable to those in control rats. However, the AUC (739, 434, and 1240 microg/min/ml) and total body clearance (67.7, 115, and 40.2 ml/min/kg) of 2-AP were significantly greater and slower, respectively, than those in control rats. This could be at least partly due to increase in S-methyltransferase activity (to form M4) in rats with PCM and greater restoration of its activity (decrease in its activity) in rats with PCMC.

Topics: Animals; Body Weight; Chromatography, High Pressure Liquid; Cysteine; Eating; Injections, Intravenous; Male; Organ Size; Protective Agents; Protein-Energy Malnutrition; Pyrazines; Rats; Rats, Sprague-Dawley; Tissue Distribution

An investigation was conducted to assess the chemopreventive effects of 2-(allylthio)pyrazine (2-AP), synthesized for potential use as a chemopreventive agent, after administration during the pre-initiation and post-initiation stages in a rat colon carcinogenesis model with azoxymethane (AOM). One hundred, 5-week-old, male F344 rats were randomly divided into two experiments (n = 50 each). Experiment 1 rats were randomly divided into three groups: Group 1 rats were pre-treated with 2-AP (25 or 50 mg/kg body weight, 3 consecutive days through the route of intragastric intubations) before AOM (20 mg/kg body weight, single subcutaneous (s.c.) injection) initiation. Group 2 rats were treated with AOM alone. Group 3 rats were given 2-AP alone without AOM initiation. The animals were killed at the end of each experiment (week 5) and the aberrant crypt foci (ACF) of the colonic mucosa were assessed after staining with methylene blue. Experiment 2 rats were randomly divided into three groups: Group 1 rats were given 2-AP (10, 25 or 50 mg/kg body weight, five-times intragastric intubations per week for 5 weeks from week 3) after AOM (15 mg/kg body weight, three s.c. injections) initiation for 2 weeks. Group 2 rats were treated with AOM alone. Group 3 rats were given 2-AP alone without AOM initiation. The animals were killed at the end of the experiment (week 8) and the ACF of the colonic mucosa were quantified. Total numbers of ACF/colon in Group 1 rats (pre-treated with 2-AP) tended to decrease (2-AP, 50 mg/kg body weight) or increase (2-AP, 100 mg/kg body weight) depending on the dose level. Total numbers of ACF/colon in Group 1 rats (treated with AOM followed by 2-AP, all subgroups; 160.8 +/- 38.0; 161.8 +/- 38.1; 137.1 +/- 48.4) were decreased significantly compared with the values in Group 2 rats (AOM alone; 214.8 +/- 48.1) (P < 0.05 or 0.01). The highest dose group (2-AP, 50 mg/kg body weight) had the lowest levels of total numbers of ACF/colon among the three subgroups. Total numbers of aberrant crypts (AC)/colon of the highest dose group (340.1+/- 117.9) decreased significantly compared with the value for Group 2 rats (AOM alone; 545.1 +/- 38.3). These results thus suggest that 2-AP may have potential as a chemopreventive agent against rat colon carcinogenesis after administration of AOM during the post-initiation stage.

Topics: Animals; Azoxymethane; Body Weight; Carcinogens; Colon; Colonic Neoplasms; Enzyme Inhibitors; Intestinal Mucosa; Male; Organ Size; Pyrazines; Rats; Rats, Inbred F344