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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↗
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↗
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↗
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

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↗
PubMed1979

Phenytoin serum levels in children with epilepsy: a micro immuno-assay technique.

The enzyme multiple immuno-assay technique (EMIT) was used to study phenytoin serum levels in 50 children with seizures. It was found that: (1) a single dose of phenytoin suspension or capsules (5mg/kg/day) produced inadequate serum levels 16 and 24 hours after ingestion, and for this reason single dosage is not recommended; (2) twice-daily dosage of phenytoin suspension or capsules (5mg/kg/day) produced adequate serum levels in most children throughout the 24 hours, and this dosage is recommended; (3) 12 children continued to have seizures but when the dose was increased to 10mg/kg/day six of the 12 obtained control of seizures; (4) phenytoin reached equilibrium in the serum in five days provided the child had not previously been taking phenobarbitone; (5) of 13 children who had been taking phenobarbitone, 10 did not achieve equilibrium of phenytoin in serum for one to four weeks; (6) phenytoin suspension given twice-daily produced satisfactory serum levels provided the bottle was shaken well before dispensing; (7) apart from minor variations, phenytoin maintained its level in serum during the 14 to 30 months follow-up period, whether 5mg or 10mg/kg/day of phenytoin was given.

Adolescent↗
PubMed1977

Phenytoin, electric, ionic, and metabolic responses in cortex and spinal cord.

Post-tetanic potentiation (PTP) of monosynaptic reflex was estimated in spinal cords in the drug-free state after the administration of a convulsant dose of penicillin and after the administration of phenytoin. There was no apparent correlation between the degree of depression of PTP and the efficacy of controlling seizure activity by phenytoin. Extracellular potassium levels were measured with ion-selective microelectrodes. The post-stimulation clearing of [K+]0 was not accelerated by phenytoin, and frequently it was slowed. Post-stimulus undershooting of [K+]0 was diminished. Oxidation of NADH in cortex and of cytochrome a, a3 in spinal cord were measured by optical methods. Stimulus-evoked transient oxidation responses evoked by electrical stimulation were depressed by phenytoin. It is concluded that systemic administration of phenytoin in therapeutic doses does not stimulate Na+-K+-activated membrane ATPase in cortex and spinal cord. Unlike other depressants, phenytoin did not cause a reduction of "resting" redox levels of respiratory enzymes. The local regulation of blood flow remained unaltered after phenytoin administration. Phenytoin caused a moderate but consistent depression of the stimulus-evoked responses of potassium activity, electric potential, and oxidative enzymes, consistent with diminished outflow of potassium from cells, owing either to lesser activation of cells or to a lesser exchange of ions.

Animals↗
PubMed1979

In vivo absorption of phenytoin from rat small intestine and its inhibition by phlorizin.

In vivo absorption of phenytoin from the small intestine was studied by an in vivo closed segment technique. Phenytoin in concentrations of 1000, 2000, and 4000 mumol/l was administered in dissolved form. Polythylene glycol 4000 was used as a non-absorbable marker. The concentrations of phenytoin in the intestinal lumen, in the mucosa, and in cardiac blood were measured both by spectrophotometry and by gas chromatography. Phenytoin was absorbed very rapidly, and the proportion absorbed increased with increasing dose. Thus, during the first 10 min. about 85 per cent of the largest dose but only 25 per cent of the smallest dose had been absorbed. The phenytoin concentration in mucosa and serum increased in an analogous way; maximum values were observed within the first ten minutes. The concentrations in mucosa and serum were dose dependent during the first ten minutes. 0.01 mmol/l and 1 mmol/l phlorizin significantly reduced the transfer of phenytoin (4000 and 2000 mumol/l) from the gut lumen to the mucosa. No inhibition was observed when the initial phenytoin dose was 1000 mumol/l. The results suggest that an active transport mechanism, sensitive to phlorizin, is involved in the intestinal absorption of phenytoin in the rat.

Animals↗
PubMed1979

Rapid metabolism of phenytoin: a method of calculating proper dosage.

The optimal dosage of phenytoin can be accurately determined by a pharmacokinetic method. By plotting the rate of administration of phenytoin acid against the apparent plasma clearance rate, we estimated the maximum rate of metabolism and the serum concentration at which the rate of metabolism was one half the maximum rate for phenytoin and then applied the Michaelis-Menten equation to optimize the dosage of phenytoin in a 48-year-old man with uncontrolled idiopathic generalized seizures and increased metabolism of phenytoin. The patient became seizure free on a regimen of 650 mg of phenytoin daily and experienced no side effects of phenytoin over-dosage. The pharmacokinetic technique described is simple to use and can be applied in an outpatient clinic.

Dose-Response Relationship, Drug↗
PubMed1975

The effect of phenytoin and ethosuximide on primidone metabolism in patients with epilepsy.

Little is known about the influence of phenytoin and ethosuximide on primidone. Therefore we studied three groups of patients: 28 receiving primidone alone, 16 on comedication of primidone with phenytoin and 9 on primidone plus ethosuximide. Antiepileptic drug determinations were done with Kupferberg's gas chromatographic method. The results show that the addition of phenytoin--but not ethosuximide--does increase the plasma concentration of phenobarbital derived from primidone but not of primidone itself. The phenobarbital/primidone plasma concentration ratio is with 4.2 +/- 0.7 (+/- S.E.) significantly (P less than 0.001) higher in patients receiving primidone and phenytoin as compared to those on primidone alone (1.6 +/- 0.2) or together with ethosuximide (1.4 +/- 0.7). The effect of phenytoin occurs and persists for several days after the steady state plasma concentration of phenytoin has been reached. This effect is probably not due to induction of enzymes hydroxylating primidone but rather to inhibition of the metabolism and/or excretion of phenobarbital. A case of phenobarbital intoxication due to addition of phenytoin to primidone medication is described in detail.

Drug Interactions↗
PubMed1979

Steady-state plasma concentrations as a function of the absorption rate and dosing interval for drugs exhibiting concentration-dependent clearance: consequences for phenytoin therapy.

Model-dependent relationships describing the effects of absorption rate and dosing interval on steady-state phenytoin plasma concentrations are presented and discussed. Utilizing a range of operative Michaelis-Menten parameters that characterize phenytoin elimination via a single capacity-limited pathway, a situation assuming instantaneous absorption (case I) is compared with the situation in which continuous constant-rate absorption occurs (case II). The results of these comparisons demonstrate that average steady-state concentrations do not differ significantly between the two cases. Ratios (case I/case II) of areas under the curve during a steady-state dosing interval substantially deviating from unity are associated with high plasma clearances and clinically low phenytoin concentrations. When the same daily dose is maintained, but the dosing interval is altered (0.25, 0.33, 0.50, 1.0 day), little difference in the average steady-state levels is observed even when absorption is instantaneous. Differences between steady-state maximum and minimum concentrations increase with prolonged dosing intervals as well as faster absorbed phenytoin formulations, but for most patients these fluctuations are therapeutically insignificant. A dimensionless parameter, Q, which is a function of the individual patient's parameters and the dosing regimen, is introduced, and its relationship with steady-state phenytoin concentrations is discussed. Formulation-related differences in phenytoin dissolution rates that may result in significantly altered absorption rates should not affect average steady-state levels unless the extent of absorption is altered. More frequent dosing is not necessary to avoid increases in the average steady-state levels when rapidly absorbed phenytoin products are administered, but may be desirable if the required daily dose is high or the individual patient exhibits a narrow therapeutic range for this drug.

Drug Administration Schedule↗
PubMed1979

Clinical and experimental studies of phenytoin-induced hyperkinesias.

Phenytoin administration occasionally leads to the induction of hyperkinetic movement disorders. The pathophysiologic basis of this phenomena is unknown, but thought to be a toxic effect of phenytoin. Study of two cases of this disorder and a review of the literature suggest that antecedant pathologic changes in the basal ganglia are prerequisites for the development of phenytoin-induced hyperkinesias. In an animal model of tardive dyskinesia, phenytoin was found to enhance neuroleptic-induced behavioral supersensitivity but have no effect in control animals. We conclude that phenytoin induced hyperkinesias reflect a specific effect of phenytoin on an abnormal neural substrate and suggest the presence of an otherwise silent pathological alteration of the corpus striatum. The diagnostic value of an episode of phenytoin-induced hyperkinesia is discussed.

Aged↗
PubMed1976

Therapeutic and pharmacokinetic effects of increasing phenytoin in chronic epileptics on multiple drug therapy.

Twenty chronic epileptics receiving phenytoin and either phenobarbitone or primidone have been studied. All patients had frequent seizures and had serum concentrations of phenytoin below 410 mumol/1. Phenytoin dosage was increased to study the effect on the frequency of seizures and the serum concentrations of phenytoin and phenobarbitone. There was no effect on minor seizures but in ten out of sixteen patients major seizures were abolished or reduced. Serum concentrations of phenobarbitone rose as the phenytoin dose was increased. This may cause deviations from the expected relationship between dose and serum concentrations of phenytoin; this would explain deficiencies which were found in a nomogram for predicting the therapeutic dose of phenytoin.

Adult↗
PubMed1978

Plasma protein binding interaction between phenytoin and valproic acid in vitro.

1 Valproic acid or phenytoin were added to fresh human serum in varying concentrations and their binding characteristics determined by the method of Scatchard (1949). 2 Changes in serum albumin binding were investigated for phenytoin in the presence of 280, 560, 1050 and 2100 mumol l-1 valproic acid, and for valproic acid in the presence of 40, 120, 280 and 480 mumol l-1 phenytoin. 3 Phenytoin appeared to bind to a single site on the albumin molecule and could be competitively displaced from this site by concentrations of valproic acid above 280 mumol l-1. 4 At high concentrations of valproic acid, the affinity of phenytoin for albumin was greatly decreased but the number of available binding sites was increased from one to four. 5 Valproic acid was bound to two high affinity and five low affinity binding sites but the latter were not detectable at valproic acid concentrations below 2100 mumol l-1. 6 Phenytoin displaced valproic acid from its high affinity binding sites, although this was statistically significant only at a concentration of 480 mumol l-1 phenytoin.

Binding Sites↗
PubMed1979

Kinetics of placentally transferred phenytoin and its p-hydroxylated metabolites in newborn infants.

1 The kinetics of phenytoin and its main metabolites, unconjugated and conjugated 4-hydroxy-phenytoin were studied in newborn infants of epileptic mothers that were treated with phenytoin during the pregnancy. 2 In two of the infants phenytoin was eliminated by an apparent zero-order process followed by an apparent first-order process. In the other two infants the mode of elimination could not be characterized. 3 The decline of plasma conjugated 4-hydroxy-phenytoin was parallel to that of phenytoin. In contrast, the plasma concentration of unconjugated 4-hydroxy-phenytoin remained grossly constant during the first 3 to 4 days.

Female↗