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At least 19 recordsLinked to original sources
PubMed1979

Effect of increased bioavailability of phenytoin tablets on serum phenytoin concentration in epileptic out-patients.

1. The bioavailability of a brand of phenytoin tablets used in Finland was improved in 1976. In the present retrospective study serum concentrations of phenytoin, measured before and after the change of bioavailability, are compared in 50 epileptic out-patients, who for various reasons used exactly the same dose of phenytoin tablets and of other drugs despite the increased bioavailability of phenytoin. 2. The mean increase of serum phenytoin steady-state concentration was about 70% after the change of bioavailability but there were considerable interindividual differences in the response. The mean increase in serum phenytoin was only 28% in patients with serum phenytoin concentrations 5 microgram/ml or less but the mean increase was 100% in patients with serum phenytoin between 5 and 10 microgram/ml. In patients with serum phenytoin concentrations more than 10 microgram/ml the mean increase in concentration was 60-80% after the improvement of bioavailability. However, in these groups of patients some clinically manifested phenytoin intoxications enforced the patients to the control and to dose reduction obviously before the steady-state concentration of phenytoin was reached. 3. On the basis of our experiences and those reported in the literature some proposals are presented to be considered when the bioavailability of phenytoin or of another drug with a narrow therapeutic range and a dose-dependent kinetics has to be changed.

Biological Availability↗
PubMed1978

Comparison of serum phenytoin levels in epileptic patients who swallowed their phenytoin tablets with or without previous chewing.

This cross-over study was conducted to compare serum phenytoin levels after chronic ingestion of phenytoin tablets with or without previous chewing. The phenytoin therapy was administered as 50 mg chewable Infatabs tablets in a single morning dose of 200 mg. There was no significant difference between the two modes of ingestion as regards serum phenytoin levels measured at various times after ingestion of the phenytoin tablets. Moreover, the area under the curve did not differ significantly during the 24 h interval. Minor changes between two Dilantin formulations, however, could influence drug availability.

Epilepsy↗
PubMed1979

Effects of pretreatment with phenobarbitone and phenytoin on the pharmacokinetics and toxicity of phenytoin on the pharmacokinetics and toxicity of misonidazole in mice.

Concentrations of the hypoxic cell radiosensitizer misonidazole (MIS) and its O-demethylated metabolite Ro 05-9963 were determined in plasma (or blood), brain and tumour after injection of 1 g/kg MIS i.p. to control mice or mice pretreated with 4-6 daily injections of phenobarbitone or phenytoin. Analysis was by high-performance liquid chromatography (HPLC). Phenobarbitone and phenytoin did not alter the peak MIS concentration in plasma, brain or tumor. However, the apparent elimination half-life (t 1/2) for MIS was reduced by 20-67%, and the area under the curve (AUC) was decreased by 23-49% in plasma, brain and tumour. The decrease in MIS t 1/2 was associated with an initially increased Ro 05-9963 metabolite concentration. However, the AUC for total 2-nitromidazole (MIS + Ro 05-9963) in plasma, tumour and brain was reduced by 20-50%. Urinary excretion of MIS and its metabolites accounted for 15-42% of the injected dose, and was unaltered by pretreatment with phenobarbitone or phenytoin. Tumour/plasm and brain/plasma concentration ratios for MIS, and tumour/plasma ratios for Ro 05-9963 were very similar, but the brain/tumour ratios for Ro 05-9963 were considerably lower. Tissue/plasma ratios were unaltered by pretreatment with phenobarbitone or phenytoin. The acute LD50 for MIS was increased from 1.54 to 1.90 g/kg after phenobarbitone pretreatment and 1.78 g/kg after phenytoin pretreatment. In addition, pretreatment with either compound shortened the duration of the MIS-induced decrease in body temperature. These data suggest that pretreatment with microsomal-enzyme-inducing agents may reduce the toxicity of MIS without affecting the radiosensitization. The significance of these findings for the mechanism of MIS toxicity is also discussed.

Animals↗
PubMed1975

Phenytoin sensitivity in a case of phenytoin-associated Hodgkin's disease.

The case of a patient who developed Hodgkin's disease three years after commencement of therapy with phenytoin is presented. Humoral and cellular immunological capacity were significantly depressed. Phenytoin caused a striking increase in DNA synthesis when lymphocytes were culture in the presence of this drug, in contrast to significant inhibition in the lymphocytes of control subjects. These findings are consistent with the hypothesis that both chronic antigenic stimulation and immunosuppression by phenytoin and involved in the induction of lymphoma.

Adult↗
PubMed1976

Sensitive GLC procedure simultaneous determination of phenytoin and its major metabolite from plasma following single doses of phenytoin.

An improved GLC procedure was developed for the simultaneous determination of phenytoin and its metabolite, 5-(p-hydroxyphenyl)-5-phenylhydantoin, in plasma and urine following enzyme hydrolysis. After extraction, the drug, the metabolite, and the internal standard, 5-(p-methylphenyl)-5-phenylhydantoin, are measured by GLC with flame-ionization detection as their respective methyl derivatives following flash-heater methylation with trimethylanilinium hydroxide. The drug and metabolite give well-resolved symmetrical peaks on a phenyl methyl silicone column, and the method has a sensitivity of 150 ng/ml of phenytoin and 125 ng/ml of the metabolite. GLC-mass spectral evidence is presented for the formation and intact determination of methyl derivatives of the drug, its metabolite, and the internal standard.

Administration, Oral↗
PubMed1975

Plasma phenytoin levels produced by various phenytoin preparations.

A cross-over study was conducted to compare the plasma phenytoin levels produced by different phenytoin preparations available in Australia. The preparations were found not to be equivalent, a liquid suspension product producing higher levels compared with capsule and tablet formulations. The clinical significance and possible explantation are discussed.

Adolescent↗
PubMed1977

Cerebellar atrophy in phenytoin-treated mentally retarded epileptics.

The relationship among the serum concentration of phenytoin, pneumoencephalographic measurements describing, in particular, cerebellar atrophy, and various other clinical variables was analyzed statistically in a series of 131 phenytoin-treated mentally retarded epileptics. Phenytoin intoxication was diagnosed retrospectively in 73 patients (56%), of whom 18 had persistent loss of locomotion. The mean duration of phenytoin intoxication until locomotion was lost was 22.8 +/- 23.6 months. There was a temporal relationship between the high serum level of phenytoin and the loss of locomotion. The degree of brain atrophy in the posterior fossa was most severe in these 18 patients with severe phenytoin intoxication. The frequency of cerebellar and/or brain stem atrophy in the present series was 28%, the same as in mentally retarded epileptics without phenytoin treatment from the same institution. That phenytoin levels in serum correlated significantly with the heights of the fourth ventricle suggests that an overdosage of phenytoin or an underlying disease, or both, were the probable causes of cerebellar impairment and atrophy. Thus brain-damaged mentally retarded epileptics appear to be unusually susceptible to the side effects of phenytoin. This antiepiliptic drug is therefore not recommended for patients with no locomotor ability or with marked cerebellar signs and symptoms. To prevent phenytoin intoxication in susceptible patients, careful observation of the patients and routine monitoring of phenytoin levels in blood are stressed.

Adolescent↗
PubMedDate not supplied

Bioavailability of phenytoin: clinical pharmacokinetic and therapeutic implications.

Phenytoin (diphenylhydantoin) is still the most commonly used anticonvulsant drug. It has certain physicochemical characteristics which make it liable to bioavailability problems. Due to the dose dependent metabolism of phenytoin and to its narrow therapeutic range even small changes in the bioavailability can cause major changes in serum phenytoin concentration and have serious clinical consequences. Numerous studies have demonstrated that there are products in general use with considerable differences in their bioavailiability. If the epilepsy is well controlled, a change from one phenytoin product to another should be avoided. Such a change might lead to phenytoin intoxication or to poor control of epilepsy, if the products do not have the same bioavailability. There seems to be no systematic difference in the bioavailability of phenytoin sodium and phenytoin acid, if products of high quality are used. On the other hand, various biopharmaceutical factors, e.g. particle size of phenytoin and the nature of excipients in the product, can have a marked effect on the oral absorption of phenytoin. Gastrointestinal diseases, the concomitant use of other drugs and dietary factors might also modify the bioavailability of phenytoin. The absorption of intramuscularly given phenytoin is rather slow and erratic. The existence of phenytoin products with different bioavailability is a serious practical problem which should be corrected as soon as possible.

Administration, Oral↗
PubMed1975

Depression of immune competence by phenytoin and carbamazepine. Studies in vivo and in vitro.

Depression of one or more parameters of cellular and/or humoral immune responses was found in 60% of general hospital patients treated with phenytoin and 47% of patients treated with carbamazepine. Phenytoin-treated patients failed to manifest delayed hypersensitivity (DHS) reactions to common antigens, and to make antibody to Salmonella typhi and tetanus toxoid. Serum levels of IgA and IgM, DNA synthesis in circulating leucocytes, and phytohaemagglutinin (PHA) induced deoxyribonucleic acid synthesis were also low. Depression of IgA, DHS reactivity and antibody responsiveness to S. typhi were shown to develop after the commencement of phenytoin therapy in a study of eleven patients. The presence of immunological defects was independent of the dosage of drug, its serum concentration, the duration of therapy and the sex of the subject. Studies in vitro provided evidence that immunosuppression was the result of a direct effect of phenytoin on the metabolism of lymphoid cells. Carbamazepine was shown to have a similar but less potent direct effect. Pharmacological concentrations of phenytoin caused a significant depression of DNA synthesis in PHA-stimulated and non-stimulated blood cell cultures in vitro. High concentrations in addition caused depression of cell counts, lymphocyte blastogenesis, ribonucleic acid and protein synthesis. Phenytoin was not cytocidal at concentrations of up to 125 mug/ml. Depression of DNA synthesis by phenytoin was maximal when phenytoin was added within 4-8 hr of the addition of PHA. PHA-induced DNA synthesis was not significantly affected by pre-incubation with phenytoin. In vivo, the presence of immunological defects was not related to phenytoin-induced folic acid deficiency. High concentrations of carbamazepine, but not phenobarbitone or diazepam caused a significant depression of PHA-stimulated DNA synthesis in blood cell cultures. The data show that immunosuppression is a common side-effect of phenytoin therapy, and that lymphoma is rare. They suggest that in the presence of phenytoin-induced immunosuppression another factor, or factors are required to induce the formation of lymphoma.

Adolescent↗
PubMed1977

The role or non-role of ATPase activation by phenytoin in the stabilization of excitable membranes.

The role or non-role of NaK ATPase, Mg ATPase, and CaMg ATPase involvement in stabilization of excitable membranes by phenytoin is critically evaluated. There is no substantial evidence to indicate that the membrane-stabilizing effect of phenytoin is due to activation of the NaK ATPase. Previous reports of activation of the NaK ATPase at low potassium and high sodium are probably not due to phenytoin but to a potassium contamination in the phenytoin solution. In vitro experiments do not provide any clear evidence of any alterations of NaK ATPase properties by phenytoin. However, one cannot rule out the possibility that phenytoin alters the efficiency of the sodium-potassium pump. Likewise, the Ca ATPase is not inhibited by phenytoin. However, there is some evidence that the Mg ATPase in synaptic vesicles is substantially inhibited by phenytoin. There is substantial evidence indicating that phenytoin partially blocks passive diffusion of sodium into stimulated nerves. The mechanism by which phenytoin blocks sodium influx and the relationship of this effect to the drug's anticonvulsant action remain to be determined.

Adenosine Triphosphatases↗
PubMed1977

Plasma protein binding and metabolic clearance of phenytoin in the rat.

The purpose [corrected] of this investigation was to determine the effects of certain changes in plasma protein binding on the disposition of phenytoin after i.v. administration in the rat. Treatment of rats with sulfisoxazole and oleic acid significantly reduced plasma protein binding of phenytoin. The displacement of phenytoin from plasma proteins by sulfisoxazole had no significant effect on the elimination of phenytoin whereas comparable displacement by oleic acid produced an increase in the apparent volume of distribution and a marked decrease in the metabolic clearance of the drug. A similar difference in metabolic clearance was noted when phenytoin elimination was determined as a function of the intrinsic ability of the rat to bind phenytoin in the plasma. Rats showing relatively high plasma protein binding of phenytoin cleared the drug much more rapidly than rats showing relatively low plasma protein binding of phenytoin. Assuming that an endogenous inhibitor is responsible for both the decreased plasma protein binding and decreased metabllic clearance of phenytoin in rats with an intrinsically reduced ability to bind phenytoin in plasma, this inhibitor is evidently similar to oleic acid in its effects.

Animals↗
PubMed1977

Bioavailability of three phenytoin preparations in healthy subjects and in epileptics.

Serum phenytoin concentrations have been studied in epileptic patients and healthy subjects taking tablets of phenytoin calcium (Desitin), A, phenytoin acid (Desitin), B, and phenytoin acid (Nordmark), C. Retrospective data and prospective investigation of hospitalized patients on long-term phenytoin treatment showed that significantly higher serum concentrations of phenytoin were produced by the phenytoin acid preparations B and C than by the phenytoin calcium preparation A. In a cross over study six volunteers received 200 mg/day of preparations A, B, and C for three weeks. In this study, too, higher phenytoin serum concentrations were produced by B and C than by A, although the differences were not statistically significant. The reasons for the discrepancies between the studies in healthy and epileptic subjects are discussed.

Adult↗
PubMed1979

The effect of different sulfonamides on phenytoin metabolism in man.

The influence on the metabolism of phenytoin of some sulfonamides given in common clinical doses has been studied. In single dose experiments sulfaphenazole increased phenytoin half-life (T/2) by 237% and decreased phenytoin metabolic clearance rate (MCR) by 67%. Sulfadiazine, sulfamethiazole, sulfamethoxazole + trimethoprim and trimethoprim increased phenytoin T/2 by 80, 66, 39 and 51% respectively, and decreased phenytoin MCR by 45, 36, 27 and 30% respectively. Sulfamethoxazole gave a small but significant increase in phenytoin T/2 but not a corresponding fall in phenytoin MCR. No changes were found in phenytoin T/2 and MCR after treatment with sulfamethoxypyridazine, sulfadimethoxine and sulfamethoxydiazine. Steady state experiments confirmed the findings of the single dose experiments. It is suggested that sulfaphenazole, sulfadiazine, sulfamethizole, sulfamethoxazole + trimethoprim and trimethoprim inhibit hepatic metabolism of phenytoin.

Adult↗
PubMed1977

Phenytoin concentrations in mixed, parotid and submandibular saliva and serum measured by radioimmunoassay.

1 Concentrations of phenytoin in mixed, parotid and submandibular saliva and serum were determined in normal subjects after an oral dose, using a specific double antibody radioimmunoassay which requires only 20 micronl fluid. 2 Semi-log concentration-time plots of phenytoin concentration in mixed saliva and serum gave good parallelism after the initial 14 h post-administration period. 3 The mean ratio of the mixed saliva: serum phenytoin concentration was 10.3% +/- 1.5 (s.d.) in seven normal subjects. 4 Phenytoin concentrations found in separate parotid and submandibular salivary fractions did not differ but were significantly greater (P less than 0.001) than those found in mixed saliva. 5 Phenytoin concentrations in all salivary fractions were independent of the volume of fluid produced and the degree of stimulation. 6 The rate of phenytoin secretion in the parotid and submandibular fluid was proportional to the salivary flow rate. 7 These data suggest that mixed saliva may be a suitable medium for the monitoring of phenytoin concentrations and may provide a non-invasive alternative to the direct determination of phenytoin in serum.

Adult↗