Effects of cysteine on the pharmacokinetics of intravenous phenytoin in rats with protein-calorie malnutrition

The effects of cysteine on the pharmacokinetics of phenytoin and one of its metabolites, 5-(p-hydroxyphenyl)-5-phenylhydantoin (pHPPH) were investigat ed after intravenous administration of phenytoin, 25 mg/kg, to control rats (4-week fed on 23% casein diet) and rats with PCM (protein-calorie malnutr ition, 4-week fed on 5% casein diet) and PCMC (PCM with oral cysteine suppl ementation, 250 mg/kg, twice daily starting from the fourth week). In rats with PCM and PCMC, the phenytoin hydroxylation (to form pHPPH) activities w ere significantly smaller (164, 103 and 95.3 pmol/min per mg protein for th e control rats, and rats with PCM and PCMC, respectively) than that in cont rol rats. In rats with PCMC, the intrinsic clearance of phenytoin, CLint wa s significantly slower than those in control rats and rats with PCM (0.175, 0.131 and 0.044 ml/min). The above data suggested that the formation of pH PPH could be reduced in rats with PCM and PCMC. This was supported by signi ficantly smaller 24-h urinary excretion of pHPPH (54.7, 35.6 and 32.5% of i ntravenous dose of phenytoin) in rats with PCM and PCMC than that in contro l rats. In rats with PCM, the maximum velocity (0.344, 0.203 and 0.196 mug/ min), apparent volume of distribution in central compartment (44.4, 65.4 an d 72.2 ml/kg) of phenytoin, and total area under the plasma concentration-t ime curve from time zero to time infinity (609, 714 and 1210 mug min/ml), r enal clearance (20.5, 13.4 and 4.67 ml/min per kg) and 24-h urinary excreti on (54.7, 35.6 and 32.5% of intravenous dose of phenytoin) of pHPPH were no t returned to control levels by cysteine supplementation (rats with PCMC). This could be mainly due to the fact that the phenytoin hydroxylation activ ity in rats with PCMC was not returned to control level. (C) 2001 Elsevier Science B.V. All rights reserved.