Pharmacokinetics of phenytoin, fosphenytoin and chloramphenicol in the rabbit and rat
Seizures commonly complicate cerebral malaria and are associated with increased risk of death and neurological sequelae. Phenytoin is used for treatment of seizures that are refractory to other treatment, but it has limitations due to its poor aqueous solubility. Its metabolism may also be inhibited by chloramphenico1. Fosphenytoin, a water-soluble phenytoin prodrug, has been introduced for clinical use. There is a n¢eed to investigate the pharmacokinetics of fosphenytoin in African children with severe malaria. A preliminary study on the pharmacokinetics of phenytoin, fosphenytoin and chloramphenicol was carried out in the rabbit and rat. Phenytoin pharmacokinetics following i.v. and i.m. administration of fosphenytoin sodium (10 mglkg phenytoin equivalents) were compared with those obtained following administration of standard phenytoin sodium injection (10 mglkg) in adult New Zealand White rabbits (N=24; 2.1±0.41 kg), anaesthetized with pentobarbitone sodium (30 mglkg). In a separate series of experiments, the effect of coadministration of chloramphenicol (25 or 50 mglkg of chloramphenicol sodium succinate) on the pharmacokinetics of phenytoin following i.v. administration offosphenytoin (30 mglkg phenytoin equivalents) xxiv was investigated in female Wistar rats (N=60; 253 .1±31. 6 g), anaesthetized with ether. In the rabbit, similar plasma phenytoin concentrations were obtained following i.v. administration of fosphenytoin, and an equivalent dose of phenytoin sodium. Median maximum plasma phenytoin concentrations (CmcvJ was 158% higher (P=0.0277) following i.m. administration of fosphenytoin sodium compared to i.m. administration of phenytoin sodium. The median area under the plasma total and free phenytoin concentration-time curve from time zero to 120 min (AUCO-120) following i.m. administration was also significantly higher (P=0.0277) in fosphenytoin treated rabbits (723.3 ug/ml.min) compared to the phenytoin (26l.2 ug/ml.min) group. However, there was no significant difference (P=0.0464) in AUCO-180 between fosphenytoin (1023.1 ug/ml.min) and phenytoin (1183.4 ug/ml.min) treated rabbits following i.v. administration. There was also no significant difference in the median times to achieve maximum plasma phenytoin concentrations (TmcvJ between fosphenytoin (30.0 min) and phenytoin (24.8 min) treated rabbits following i.m. administration (P=O.675). Mean plasma albumin concentrations were comparable in both groups of animals (P=0.9304). Fosphenytoin was rapidly converted to phenytoin both after i.v. and i.m. administration, with plasma fosphenytoin concentrations declining rapidly to undetectable concentrations within 10 min xxv following administration via either route. These results confirm the rapid and complete hydrolysis of fosphenytoin to phenytoin in vivo, and the potential of the i.m. route for administration of fosphenytoin delivering phenytoin in clinical settings where i.v. administration is not feasible. Following i.v. administration of fosphenytoin in rats, plasma phenytoin concentrations were similar to those obtained after coadministration of fosphenytoin and 25 mg/kg of chloramphenicol succinate (P=O.281). The AUCO-7h was approximately 9% and 60% higher following coadministration of fosphenytoin and 25 and 50 mg/kg of chloramphenicol succinate, respectively. Chloramphenicol concentrations were approximately twofold higher after administration of 50 mg/kg compared to 25 mg/kg, but were below the reported therapeutic range (10-20 ug/ml). The AUCo-Th was 11.30 and 20.54 ug-h/ml following administration of 25 and 50 mg/kg of chloramphenicol succinate, respectively. The results confirm that both fosphenytoin and chloramphenicol succinate are quantitatively hydrolyzed in vivo in the rat, and that the interaction between phenytoin and chloramphenicol in vivo in the rat is dose-dependent. The results of this study emphasize the importance of monitoring the plasma concentrations of phenytoin when it is concurrently administered with chloramphenicol in clinical practice.