Phenytoin Prodrugs VI: In Vivo Evaluation of a Phosphate Ester Prodrug of Phenytoin after Parenteral Administration to Rats

Varia, Sailesh A.; Stellax, V.J.

doi:10.1002/jps.2600730815

Cited by 38 publications

(8 citation statements)

References 15 publications

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“…The mean area under the plasma concentration-time (AUC O _ 18 0 ) after i.v administration of fosphenytoin was 90.2%of that following i.v administration of phenytoin sodium, suggestingalmost complete hydrolysis of fosphenytoin to phenytoin in the rabbit. These results are consistent with previous findings (22,23) in the beagle dog and rat. It should be pointed out that AVC was calculated by assuming that the pharmacokinetics of phenytoin were not saturable at the dose used in the present study.…”

Section: Discussionsupporting

confidence: 83%

Pharmacokinetics of phenytoin following intravenous and intramuscular administration of fosphenytoin and phenytoin sodium in the rabbit

Muchohi

Kokwaro

Maitho

et al. 2002

Eur. J. Drug Metab. Pharmacokinet.

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The purpose of this study was to evaluate and compare plasma phenytoin concentration versus time profiles following intravenous (i.v.) and intramuscular (i.m.) administration of fosphenytoin sodium with those obtained following administration of standard phenytoin sodium injection in the rabbit. Twenty-four adult New Zealand White rabbits (2.1 +/- 0.4 kg) were anaesthetized with sodium pentobarbitone (30 mg/kg) followed by i.v. or i.m. administration of a single 10 mg/kg phenytoin sodium or fosphenytoin sodium equivalents. Blood samples (1.5 ml) were obtained from a femoral artery cannula predose and at 1, 3, 5, 7, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240 and 300 min after drug administration. Plasma was separated by centrifugation (1000 g; 5 min) and fosphenytoin, total and free plasma phenytoin concentrations were measured using high performance liquid chromatography (HPLC). Following i.v. administration of fosphenytoin sodium plasma phenytoin concentrations were similar to those obtained following i.v. administration of an equivalent dose of phenytoin sodium. Mean peak plasma phenytoin concentrations (Cmax) was 158% higher (P = 0.0277) following i.m. administration of fosphenytoin sodium compared to i.m. administration of phenytoin sodium. The mean area under the plasma total and free phenytoin concentration-time curve from time zero to 120 min (AUC(0-120)) following i.m. administration was also significantly higher (P = 0.0277) in fosphenytoin treated rabbits compared to the phenytoin group. However, there was no significant difference in AUC(0-180) between fosphenytoin and phenytoin-treated rabbits following i.v. administration. There was also no significant difference in the mean times to achieve peak plasma phenytoin concentrations (Tmax) between fosphenytoin and phenytoin-treated rabbits following i.m. administration. Mean plasma albumin concentrations were comparable in both groups of animals. Fosphenytoin was rapidly converted to phenytoin both after i.v. and i.m. administration, with plasma fosphenytoin concentrations declining rapidly to undetectable levels within 10 min 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 may not be feasible.

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Section: Discussionsupporting

confidence: 83%

Pharmacokinetics of phenytoin following intravenous and intramuscular administration of fosphenytoin and phenytoin sodium in the rabbit

Muchohi

Kokwaro

Maitho

et al. 2002

Eur. J. Drug Metab. Pharmacokinet.

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“…clindamycin phosphate and phenytoin phosphate (Fig. 11 ) [ 11 ]. The prodrug concept may be utilized to alter the solubility of a drug.…”

Section: Pharmaceutical Applicationmentioning

confidence: 99%

Prodrugs of NSAIDs: A Review

Shah¹,

Gupta²,

Chauhan³

et al. 2017

TOMCJ

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Intoroduction:Prodrug approach deals with chemical biotransformation or enzymatic conversion or involves inactive or less active bio-reversible derivatives of active drug molecules. They have to pass through enzymatic or chemical biotransformation before eliciting their pharmacological action.Methods & Materials:The two different pharmacophores combine to give synergistic activity or may help in targeting the active drug to its target. Prodrug super seeds the problems of prodrug designing, for example solubility enhancement, bioavailability enhancement, chemical stability improvement, presystemic metabolism, site specific delivery, toxicity masking, improving patient acceptance, or eradicating undesirable adverse effects.Results:As an outcome the search for a prodrug or mutual prodrug with reduced toxicity has continued during recent years. This present review emphasizes the common help to revamp physiochemical, pharmaceutical and therapeutic effectiveness of drugs.Conclusion:This gives the researcher a common platform where they can find prodrugs of commonly used NSAIDs to overcome the gastrointestinal toxicity (irritation, ulcergenocity and bleeding).

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“…Although the prodrug was evaluated at Parke‐Davis by a group led by Anthony (Tony) Glazko and proven to be an effective prodrug of phenytoin,3 it was not commercially pursued because it showed a transitory cardiovascular effect that was traced to the prodrug itself. It was only later that we successfully developed fosphenytoin as a safe and effective parenteral prodrug alternative to sodium phenytoin 4, 5…”

Section: A Historical Perspectivementioning

confidence: 99%