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

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.     

Piperine in food: interference in the pharmacokinetics of phenytoin.

This study was carried out to explore the effect of piperine-containing food in altering the pharmacokinetics of phenytoin, an anti-epileptic drug with a narrow therapeutic index. A preliminary pharmacokinetic study was carried out in mice by administering phenytoin (10 mg) orally, with or without piperine (0.6 mg). Subsequently, oral pharmacokinetics of phenytoin was carried out in six healthy volunteers in a crossover design. Phenytoin tablet (300 mg) was given 30 minutes after ingestion of a soup (melahu rasam) with or without black pepper. A further study of intavenous pharmacokinetics of phenytoin (1 mg) in rats with or without oral pretreatment with piperine (10 mg) was also conducted. The phenytoin concentration in the serum was analyzed by HPLC. The study showed a significant increase in the kinetic estimates of Ka, AUC(0-10) and AUC(0-infinity) in the piperine-fed mice. Similarly, in human volunteers piperine increased Ka, AUC(0-48), AUC(0-infinity), and delayed elimination of phenytoin. Intravenous phenytoin in the oral piperine-treated rat group showed a significant alteration in the elimination phase indicating its metabolic blockade. The significance of this finding in epileptic patients maintained on phenytoin therapy requires further investigation. This study may also have implications in the case of other drugs having a low therapeutic index.     

Bayesian regression analysis of non-steady-state phenytoin concentrations: evaluation of predictive performance

Michaelis-Menten saturable pharmacokinetics confound the determination of appropriate phenytoin maintenance doses. This study retrospectively evaluated the performance of an IBM-PC/XT computer program applying Bayesian regression to the "explicit solution to the Michaelis-Menten equation." Zero to five non-steady-state phenytoin serum concentrations were used to predict either non-steady-state concentrations at least 10 days in the future (n = 49) or steady-state concentrations (n = 20). Non-steady-state concentration prediction precision (% mean absolute error) using 0-5 non-steady-state feedbacks was 137%, 62%, 39%, 31%, 25%, and 15%, respectively, and steady-state concentration prediction precision was 446%, 47%, 50%, 44%, 21%, and 13%, respectively. Elimination of subjects receiving concurrent drugs known to induce phenytoin metabolism significantly improved predictions based on population priors; however, performance improvements were not apparent after two serum level feedbacks. The program provided clinically acceptable predictions with four or more feedbacks. Refinement of population parameters and optimal sampling times should further improve performance.     

Influence of food on the absorption of phenytoin in man

Summary The influence of food intake on the absorption of phenytoin was examined in eight healthy volunteers, by study of single-dose kinetics following ingestion of phenytoin 300 mg either with a standardized breakfast or on an empty stomach. Blood samples were collected at regular intervals from 0 to 48 h, and serum concentrations of unmetabolized phenytoin were determined by gas chromatography. Serum concentrations of the major metabolite of phenytoin, 4-hydroxyphenytoin, were measured by mass fragmentography. Concurrent intake of food and phenytoin appeared to accelerate absorption of the drug from the formulation used, and the peak concentrations were significantly higher (mean increase 40%) in the postprandial than in the preprandial state. As reflected by the AUC (area under the curve), the amount of drug absorbed was increased during postprandial conditions, although the difference only reached borderline significance. It is suggested that phenytoin should always be taken in a defined relation to meals.     

乙醇对苯妥英钠药代动力学的影响

目的 :观察乙醇对苯妥英钠药代动力学的影响。方法 :分别对8只家兔单用苯妥英钠和乙醇合用后苯妥英钠的药代动力学参数变化进行研究和比较 ,采用紫外分光光度法测定苯妥英钠的经 -时血药浓度 ,以“3p87”程序拟合药代动力学参数。结果 :合用乙醇后 ,苯妥英钠的AUC由 (4108 64±1039 98)ml/(L·min)降至 (1903 65±1003 40)mg/(L·min) ;T1/2(ke)由 (98 45±26 4)min降至 (82 84±25 5)min ;Vd 由 (0 3475±0 0360)L/kg升至 (0 6819±0 1901)L/kg ;CLs 由 (0 0026±0 0008)ml/(kg·min)升至(0 0062±0 0022)ml/(kg·min) ;Cmax 由 (29 0±2 94)mg/L降至 (16 0±5 9)mg/L。结论 :合用乙醇后 ,苯妥英钠的消除在体内明显加快     

Absorption of phenytoin from rectal suppositories formulated with a polyethylene glycol base

STUDY OBJECTIVE: To compare phenytoin pharmacokinetics following administration of an oral suspension and a rectal suppository formulated with a polyethylene glycol base. DESIGN: Unblinded, single-dose, randomized, crossover trial. SETTING: University-affiliated pharmacokinetics and biopharmaceutics laboratory. SUBJECTS: Six healthy subjects. INTERVENTION: Subjects were given a single 200-mg dose of phenytoin as an oral suspension and a rectal suppository separated by a 1-week washout. MEASUREMENTS AND MAIN RESULTS: Blood for plasma phenytoin concentrations was obtained at baseline and 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours after administration. Plasma was analyzed by high-performance liquid chromatography (coefficient of variation < 6%) for total phenytoin concentration. Phenytoin maximum concentration (Cmax), time to Cmax (Tmax), time to first measurable concentration (Tlag), and area under the curve from time zero to time of last measurable concentration (AUClast) were estimated for oral and rectal administration by WinNonlin (v 1.1) and compared using Wilcoxon's signed rank test (p<0.05 for statistical significance). Two subjects did not have detectable plasma phenytoin concentrations after rectal administration. For the other four subjects, median rectal Cmax was significantly lower than oral Cmax (0.4 vs 1.9 microg/ml, p=0.028), median rectal Tmax did not differ from oral Tmax (11.9 vs 8.0 hrs, p=0.465), and median rectal AUClast, although highly variable, was significantly lower than oral AUClast (5.4 vs 36.2 microg x hr/ml, p=0.046). No Tlag was seen after oral administration, but with rectal administration the median Tlag was 2 hours. The estimated relative bioavailability of rectal phenytoin suppositories based on AUC0-24 was 4.7%, with individual values ranging from 0-58.3%. CONCLUSION: It appears that absorption of phenytoin from polyethylene glycol rectal suppositories in healthy subjects is highly variable and unpredictable. Thus this formulation is not recommended.     

Absorption characteristics of three phenytoin sodium products after administration of oral loading doses

The absorption characteristics of three phenytoin sodium products given orally as loading doses in five healthy men were studied. Extended phenytoin sodium capsules, prompt phenytoin sodium capsules, and phenytoin sodium injection were administered in a randomized, crossover trial as single 18-mg/kg doses and as divided doses of 6 mg/kg every three hours for three doses. Each dose was given with 200 ml of water, and a two-week washout period followed each treatment. The maximum plasma concentration (Cmax), time to reach maximum plasma concentration, time to reach the lower end (10 mg/liter) of the therapeutic range, time to reach a plasma concentration greater than 15 mg/liter, and time within the therapeutic range were determined for each loading-dose regimen. Prompt phenytoin sodium capsules (prompt PHT) given in divided doses produced a mean Cmax of 22.0 mg/liter, which was significantly higher than that observed with any of the other loading-dose regimens. In addition, all subjects receiving prompt PHT in divided doses had plasma phenytoin concentrations of 10 mg/liter within six hours; only this treatment produced plasma concentrations greater than 15 mg/liter at nine hours in all subjects. Plasma concentrations remained within the therapeutic range (10-20 mg/liter) for 81 and 78% of the first 24-hour period for prompt PHT in divided and single doses, respectively. Adverse effects were minimal in all regimens. The prompt-release phenytoin sodium capsules used in this study may provide an alternative means for rapidly achieving therapeutic phenytoin concentrations in situations where i.v. administration is not indicated or practical.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antipyretic analgesics in patients on antiepileptic drug therapy

Summary The effect of administration for three days of acetylsalicylic acid (1500 mg/day), phenylbutazone (300 mg/day), paracetamol (1500 mg/day) and tolfenamic acid (300 mg/day) on serum concentrations of phenytoin and carbamazepine were studied in a group of patients on continuous antiepileptic therapy. When measured 10 h after the last dose of the analgesics, the only significant effect was a decrease in total serum phenytoin after three days of phenylbutazone. When six patients on continuous phenytoin therapy took phenylbutazone for two weeks there was at two days an initial decrease, followed by a significant increase in total serum phenytoin and a concomitant increase in free phenytoin in serum. Even phenylbutazone was well tolerated by most of the patients. However, its use had to be discontinued in one patients due to obvious signs of phenytoin intoxication, with concomitant increases in the serum free and total phenytoin concentrations.     

Brain concentrations of phenytoin,phenobarbitone and primidone in epileptic patients

Summary Plasma, brain, lumbar CSF, skeletal muscle, skin and bone concentrations of phenytoin, phenobarbitone and primidone have been measured in specimens from patients undergoing temporal lobectomy for chronic epilepsy. A good correlation was found between the plasma and brain concentrations of each drug. Similarly, a good correlation was found between the plasma and CSF concentrations of each drug. Assuming that CSF is an ultrafiltrate of plasma, the percentage of phenytoin, phenobarbitone and primidone which was unbound in plasma was 10–14%, 43% and 81% respectively. Skeletal muscle concentrations of phenytoin and phenobarbitone and the skin concentration of phenytoin, also correlated with the plasma concentrations, but the remaining tissues did not give significant correlations.     

Effect of saliva flow rate on saliva phenytoin concentrations: implications for therapeutic monitoring

The effect of atropine-induced reductions in saliva flow rate on saliva phenytoin concentrations were evaluated in a randomised placebo-controlled crossover study in a group of epileptic patients stabilised on the drug.Pretreatment with atropine caused significant reductions in saliva flow rates during the first 4 h, compared to saline. The AUC_{0–4 h} for saliva flow rate was significantly reduced by atropine (245 g vs 327 g) and the saliva phenytoin AUC_{0–4 h} was significantly increased (5.6 g · ml^–1 · h vs 4.5 g · ml^–1 · h) without affecting plasma phenytoin concentrations. The saliva/plasma phenytoin AUC_{0–4 h} ratio was therefore significantly increased by atropine (0.15 vs 0.12). However, there was a poor correlation between saliva/plasma phenytoin concentration ratios and saliva flow rates for the two treatments in the individual patients (correlation coefficient ranged from 0.25 to 0.65).These findings demonstrate that saliva phenytoin concentrations are increased by reductions in saliva flow rate. Caution is therefore required when saliva phenytoin concentrations are used for therapeutic monitoring in the presence of factors which may affect saliva flow rate.     

Phenytoin dose adjustment in epileptic patients

1 A preliminary survey showed that many outpatients with partially controlled epilepsy had serum concentrations of phenytoin below the recommended therapeutic range (10-20 μg/ml). A phenytoin tolerance test was devised with the intention of predicting a more adequate daily dose for such a patient.

2 Fifteen patients were each given an oral test dose of 600 mg phenytoin sodium and the serum concentration of phenytoin was measured at intervals over 48 h; the concentration rose during the first 4 h and decayed between 12-48 h as an almost linear function of time.

3 The serum concentration/time curves were fitted by an interative computer program based on the Michaelis-Menten equation. The mean saturated rate of elimination of phenytoin was 435 mg/day and the serum concentration (K_m) corresponding with 50% saturation was 3.8 μg/ml. The mean calculated dose of phenytoin sodium required for a steady state serum concentration of 10-20 μg/ml was 345-400 mg/day.

4 The Michaelis-Menten principle was used to predict steady state serum phenytoin concentrations in individual patients receiving daily doses of phenytoin sodium adjusted by steps of 100 mg. The serum concentrations tended to be either too low or too high. The steep relationship between phenytoin concentration and dose indicates that when the concentration reaches 5-10 μg/ml it is then appropriate to adjust dose by small steps of about 25 mg.

     

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.     

Evaluation of serum phenytoin monitoring in an acute care setting

Serum phenytoin monitoring is frequently used in the management of epileptic patients because phenytoin has a narrow therapeutic index and exhibits nonlinear pharmacokinetics. This study prospectively evaluated serum phenytoin monitoring in an acute care teaching hospital. Two sets of criteria were established a priori to define (a) appropriate selection of patients with regard to serum phenytoin monitoring, and (b) inappropriate serum phenytoin determinations (SPDs). Eighty patients receiving phenytoin were studied, of whom 58 (72.5%) were appropriately selected. These included 35 patients (43.8%) for whom monitoring was indicated and was performed, and 23 patients (28.7%) for whom monitoring was not indicated and was not performed. There were 39 patients with no indications for serum phenytoin monitoring; however, 16 (41%) of them were monitored. A total of 113 SPDs were performed, of which 83 (73.5%) were deemed to be inappropriate. Seventy percent of SPDs resulted in phenytoin concentrations outside the usual therapeutic range (10-20 micrograms/ml). Overall, physicians appropriately selected patients with regard to serum phenytoin monitoring; however, when inappropriate selection did occur, it tended to involve monitoring of patients who did not require it. The majority of SPDs performed were deemed to be inappropriate, since they were done too soon after admission or a change in therapy to reliably indicate steady-state serum concentrations.     

Influence of enteral feedings on phenytoin sodium absorption from capsules

The influence of enteral feedings (with Ensure) on the absorption of phenytoin sodium from capsules was studied. Six healthy adult volunteers were given a single dose of phenytoin capsules 400 mg po on two occasions. Blood specimens were collected for 48 hours after each dose. In a randomized, crossover fashion, each subject completed the following two phases: (1) phenytoin without enteral feedings, and (2) concomitant enteral feedings before phenytoin and continued at 100 ml/h for ten hours. The areas under the concentration versus time curves from 0-48 hours (AUC0-48) were not significantly different between the two phases (p greater than 0.5). The percent relative bioavailability of phenytoin with enteral feedings was 101.7 percent. This study suggests that enteral feedings do not affect the serum concentrations of phenytoin after a single dose given in capsule form.     

Effect of serum separator tubes on free and total phenytoin and carbamazepine serum concentrations

The effect of serum separator tubes (SSTs) on free and total serum phenytoin and carbamazepine concentrations was determined by comparing standard no-additive tubes with SSTs (Becton Dickinson SST and Terumo Autosep). The influence of time prior to centrifugation, sample volume, and initial drug concentration on the effects were also studied. Results were analyzed using repeated measures two-way analysis of variance with tube type and either time, sample volume, or concentration as main effects. The most significant reductions noted were with Becton Dickinson SSTs in free and total serum phenytoin and total carbamazepine concentrations, where all reductions were less than 10%. The only factor to significantly influence extent of reduction was the effect of time on total serum phenytoin concentration in Becton Dickinson SSTs. Terumo Autosep tubes caused no major reductions in free or total phenytoin or carbamazepine serum concentrations. Autosep tubes should provide accurate measurements of total and free serum phenytoin and carbamazepine concentrations. With Becton Dickinson SSTs, the reductions noted in free and total phenytoin and total carbamazepine concentrations were not large enough to preclude their clinical use. Becton Dickinson SSTs should not be used for determining free or total phenytoin or total carbamazepine concentrations for purposes of research.     

Concomitant use of mirtazapine and phenytoin: a drug-drug interaction study in healthy male subjects

OBJECTIVE: The objectives of this study were to assess the effect of mirtazapine on steady-state pharmacokinetics of phenytoin and vice versa and to assess tolerability and safety of the combined use of mirtazapine and phenytoin. METHODS: This was an open-label, randomised, parallel-groups, single-centre, multiple-dose pharmacokinetic study. Seventeen healthy, male subjects completed either treatment A [nine subjects: daily 200 mg phenytoin for 17 days plus mirtazapine (15 mg for 2 days continuing with 30 mg for 5 days) from day 11 to day 17] or treatment B [eight subjects: mirtazapine, daily 15 mg for 2 days continuing with 30 mg for 15 days plus phenytoin 200 mg from day 8 to day 17]. Serial blood samples were taken for kinetic profiling on the 10th and 17th days of treatment A and on the 7th and 17th days of treatment B. Induction of CYP 3A by phenytoin was evaluated by measuring the ratio of 6 beta-hydroxycortisol over cortisol on the 1st, 7th and 17th days of treatment B. RESULTS: Co-administration of mirtazapine had no effect on the steady-state pharmacokinetics of phenytoin, i.e. the area under the plasma concentration-time curve (AUC)(0-24) and peak plasma concentration (C(max)) remained unchanged. The addition of phenytoin to an existing daily administration of mirtazapine resulted in a mean (+/-SD) decrease of the AUC(0-24) from 576+/-104 ng h/ml to 305+/-81.6 ng h/ml and a mean decrease of C(max) from 69.7+/-17.5 ng/ml to 46.9+/-10.9 ng/ml. Induction of CYP 3A by phenytoin is confirmed by the significantly ( P=0.001) increased 6beta-hydroxycortisol/cortisol ratio from 1.74+/-1.00 to 2.74+/-1.64. CONCLUSION: Co-administration of mirtazapine did not alter the steady-state pharmacokinetics of phenytoin. The addition of phenytoin to an existing daily administration of mirtazapine results in a decrease of the plasma concentrations of mirtazapine by 46% on average, most likely due to induction of CYP 3A3/4.     

In Vivo Absorption of Phenytoin from Rat Small Intestine and its Inhibition by Phlorizin

Abstract 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 μmol/1 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 percent 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/1 and 1 mmol/1 phlorizin significantly reduced the transfer of phenytoin (4000 and 2000 μmol/1) from the gut lumen to the mucosa. No inhibition was observed when the initial phenytoin dose was 1000 μmol/1. The results suggest that an active transport mechanism, sensitive to phlorizin, is involved in the intestinal absorption of phenytoin in the rat.     

Concentration-time profile of phenytoin after admixture with small volumes of intravenous fluids

A study was designed to determine if admixtures with small volumes of four intravenous fluids (0.45% sodium chloride, 0.9% sodium chloride, 5% dextrose in water and lactated Ringer's) maintain their phenytoin concentrations over a suitable period of time to allow intravenous infusion of the drug. Three phenytoin concentrations (4.6 mg/ml, 9.2 mg/ml and 18.4 mg/ml) were prepared by adding a sufficient volume of an i.v. fluid to the appropriate volume (10.0, 20.0 and 40.0 ml) of phenytoin sodium injection (46 mg of phenytoin acid/ml) to produce a total volume of 100 ml. Each admixture was visually inspected for crystallization, the pH of each solution was determined, and the solutions were filtered through a 0.22-micrometer micropore filter. Unfiltered and filtered aliquots of all solutions were collected at 0, 0.25, 0.5, 1, 4, 8 and 24 hours following admixture. Phenytoin concentrations did not decline systematically during this period nor was there a significant difference (p greater than 0.05) between unfiltered and filtered aliquots in any of the solutions studied, except for the 9.2 mg/ml concentration of 5% dextrose in water. The phenytoin concentrations in the 5% dextrose in water and lactated Ringer's solutions showed the greatest variability over the 24-hour period. The pH for all solutions ranged from 10.15 to 11.50. One-half normal saline and normal saline in small volumes appear to be suitable vehicles for intravenous infusion of phenytoin.     

3H]Phenytoin identifies a novel anticonvulsant-binding domain on voltage-dependent sodium channels.

The voltage-dependent sodium channel has been proposed as a specific target for the actions of the anticonvulsant drug phenytoin. Working at 0-4 degrees, we previously reported the existence of specific [3H]phenytoin binding sites in rat brain membranes. In the present study, the binding of [3H]phenytoin was assessed at 22 degrees, a temperature favorable to the binding of sodium channel ligands. At 22 degrees, the site had a Kd of 1.5 microM, which is in the relevant therapeutic concentration range for anticonvulsant activity (1-10 microM), and a calculated Bmax of 4.5 pmol/mg of protein, which is similar to previous estimates of sodium channel concentration in brain membranes. In competition experiments, specific [3H]phenytoin binding was found to be inhibited by drugs that interact with the sodium channel, including antiarrhythmics, local anesthetics, anticonvulsants, and site-specific neurotoxins (the steroidal alkaloid activators, beta-scorpion venoms, and brevetoxin-3). Diazepam, used clinically in the management of tonic-clonic status epilepticus, and flunarizine, a calcium channel blocker with anticonvulsant activity, potentiated [3H]phenytoin binding at micromolar concentrations. Other drugs and ligands, including neurotransmitters, neuromodulators, and ligands for other ion channels, had no effect. Depolarization with KCl showed [3H]phenytoin binding to be voltage sensitive. Experiments with batrachotoxin (a specific site 2 toxin) and anticonvulsants demonstrated that the interactions between these compounds and the [3H]phenytoin binding site are allosteric in nature. These results provide direct evidence that phenytoin interacts with the voltage-dependent sodium channel and indicate that such interactions take place at therapeutic concentrations. They support previous proposals, based on toxin-binding and electrophysiological studies, that the therapeutic effects of phenytoin result from a selective inhibition of voltage-dependent sodium flux.     

Phenytoin: an inhibitor and inducer of primidone metabolism in an epileptic patient.

The interaction between primidone and phenytoin was studied in an epileptic patient treated with primidone only and primidone plus phenytoin for 3 months. Plasma and urine levels of drugs and metabolites were monitored daily by GC and GC-MS. The addition of phenytoin to the regimen increased steady-state plasma levels of phenobarbitone and phenylethylmalonamide (PEMA), metabolites of primidone, and decreased levels of primidone and unconjugated p-hydroxyphenobarbitone (p-OHPB), a metabolite of phenobarbitone. After withdrawal of phenytoin, plasma phenobarbitone and primidone levels slowly returned to previous steady-state levels, PEMA rapidly decreased to lower levels than before, and p-OHPB levels rose rapidly. Urinary excretion of primidone and its metabolites paralleled the changes in their plasma levels after the addition of phenytoin but the percentage of unconjugated p-OHPB in urine was unchanged during the course of the study. In conclusion phenytoin initially induces the conversion of primidone to PEMA and phenobarbitone, although each to a different extent, but it appears to inhibit the hydroxylation of phenobarbitone. Thus, two apparently contradictory phenomena seem to be involved in the primidone-phenytoin interaction. The net effect is an enhanced increase in plasma phenobarbitone levels.