Effects of cysteine on the pharmacokinetics of intravenous 2-(allylthio)pyrazine, a new chemoprotective agent, in rats with protein-calorie malnutrition.

摘要

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.