| dc.description.abstract | 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)
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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
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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. | en |
