Phenytoin Toxicity Due to Genetic Polymorphism

Introduction  Patients with traumatic brain injury commonly receive phenytoin for seizure prophylaxis. Due to the non-linear pharmacokinetics of phenytoin and narrow therapeutic window, phenytoin concentrations are monitored to ensure efficacy and prevent toxicity. Because phenytoin is hepatically metabolized, polymorphisms within cytochrome P450 enzymes can affect phenytoin concentrations. Methods  We report a case of a 53-year-old Asian female admitted to the neuroscience intensive care unit after suffering a traumatic brain injury. Phenytoin was subsequently administered for seizure prophylaxis. Results  Four days after being initiated on phenytoin, the patient remained lethargic, and phenytoin toxicity was suspected. Lab values revealed a free phenytoin concentration of 4.4 mg/l, and phenytoin was discontinued. Upon further investigation, it was found that the patient was a cytochrome P450 2C9 poor metabolizer. Causes of the patient’s toxic phenytoin concentration such as drug interactions, decreased albumin, and lab error were excluded. The cause of her elevated phenytoin concentration was determined to be hepatic polymorphism. Conclusion  This case reveals the clinical significance of genetic polymorphisms and the effect on phenytoin dosage requirements. Because pharmacogenomic testing is expensive and not readily available, routine monitoring of phenytoin concentrations is warranted. Further, established polymorphisms should be documented to prevent toxicity of drugs metabolized by similar pathways.     

Effect of Acute and Chronic Terfenadine on Free and Total Serum Phenytoin Concentrations in Epileptic Patients

Terfenadine is a unique H1-receptor antagonist devoid of adverse central nervous system (CNS) effects. Terfenadine is highly protein bound and has been shown to stimulate hepatic microsomal enzymes, making an interaction with phenytoin (PHT) possible. After assuring constant PHT levels for 7 days, 12 epileptic patients were studied with PHT alone, after a single daily dose of terfenadine (60 mg twice daily), and again after 2 weeks of chronic terfenadine therapy. Samples for PHT were drawn over 24 h, and urine was collected for determination of the PHT metabolite 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH). The pharmacokinetic parameters calculated for total and free PHT and HPPH were area under the time concentration curve (AUC), the maximum serum concentration (Cmax), the minimum serum concentration (Cmin), and the percentage of fluctuation between maximum and minimum concentrations. A factor analysis was used to clarify interrelationships. Five dependent variables were found to represent the data. These were assessed by multi-variate analysis of variance (MANOVA); p less than 0.05 was considered significant. No significant differences were observed for any of the parameters for the acute or chronic effects of terfenadine. We conclude that terfenadine does not interfere with PHT.     

Pharmacokinetics of W-554 (ADD 03055) in Epileptic Patients

W-554 (ADD 03055, 2-phenyl-1,3-propanediol dicarbamate) has broad-spectrum antiepileptic activity in animal models of epilepsy. We evaluated its pharmacokinetics and toxicity as an adjunctive medication in eight adult male patients with uncontrolled seizures, treated with phenytoin (n = 4) or carbamazepine (n = 4). After a single 200-mg dose, peak W-554 serum levels of 2.65-4.10 mg/L were achieved in 1-4 h. Half-lives were 11.2-16.1 h and clearance varied from 34.2-64.6 ml/h X kg. The apparent volume of distribution was 0.726-1.046 L/kg. Chronic dosing at 400, 800, 1,200, and 1,600 mg/day resulted in median steady-state trough levels of 5.1, 10.2, 14.6, and 20.3 mg/L. A second kinetic study at the end of chronic dosing indicated no change in volume of distribution, decreased clearance, and increased half-life, compared with single dose data. Urinary excretion of unchanged drug was 13.8-28.6% of the dose. Only one subject had toxicity (mild blurred vision and tremor) possibly attributable to W-554. Seizure control was improved in six of eight subjects, and seizures were less severe in three, while on W-554. Addition of W-554 resulted in increases in serum phenytoin levels, and small decreases in serum carbamazepine levels.     

苯妥因钠,丙戊酸钠,卡马西平对癫痫患者智力的影响

抗癫痫药物造成认知功能的损害及损害程度至今仍无明确结果。为此，我们对４６例全身性强直一阵挛发作的癫痫患儿进行了服药前后的智力测验，并以１６例健康同龄人对照，以检测苯妥历钠，丙戊酸钠，卡马西平对智力的影响。     

Periodontal Condition of Epileptic Adults Treated Long-Term with Phenytoin or Carbamazepine

The periodontal condition of 40 adult epileptic subjects (mean age 51 years) receiving long-term therapy (mean 18 years) with phenytoin (PHT) or carbamazepine (CBZ) was studied. The subjects completed a questionnaire and underwent clinical and radiologic examination. Patients receiving PHT exhibited the same level of alveolar bone loss as those receiving CBZ. Patients receiving PHT exhibited more units with gingival overgrowth, reflected by the significantly higher number of gingival units with increased probing depth (p < 0.05). The results indicate that long-term PHT does not result in increased risk for alveolar bone loss as compared with CBZ.     

Alterations of Ballistic Movements in Epileptic Patients with Phenytoin Intoxication

We assessed the effects of phenytoin (PHT) overdosage on ballistic arm abduction movements in nine epileptic patients receiving long-term PHT treatment. During the overdosage period, all but one showed clinical abnormalities referable to impaired cerebellar function; one also had slowness of movement. Ballistic movements showed abnormalities in all of the patients although a great variability was present in the type and severity of abnormalities. In four patients, kinematic and EMG recordings differed least from the normal, in four they resembled those described in patients with cerebellar deficits, and in one those described in patients with Parkinson disease. The type and severity of clinical disturbances of voluntary motor control as well as alterations of ballistic movements were not related to specific PHT plasma concentrations. One month after the adjustment of PHT dosage, the patients who had clinical abnormalities completely recovered or markedly improved. Previously observed kinematic and EMG abnormalities completely disappeared or improved markedly.     

A Comparison of Phenytoin Dosing Methods in Private Practice Seizure Patients

In an attempt to evaluate the accuracy of phenytoin (PHT) pharmacokinetic dosage adjustments in a private practice setting, three single dose-concentration pair methods and three multiple point PHT pharmacokinetic dosing methods were studied. Dose and concentration data from 28 patients seen in a private neurology practice were utilized for the study. From a comparison of these methods in private practice seizure patients, it appears that the Bayesian feedback method may be the most accurate in making routine PHT dosage adjustments, perhaps by minimizing the contribution of unknown variables within the Bayesian approach.     

Pharmacological Interactions of Mesuximide with Phenobarbital and Phenytoin in Hospitalized Epileptic Patients

In order to study the pharmacological interactions of the anticonvulsant drugs mesuximide (MSM), phenobarbital (PB), and phenytoin (PHT), serum concentrations of N-desmethyl-mesuximide (N-DESM-MSM, the main metabolite of MSM), PB, and PHT were determined in 94 hospitalized patients suffering from petit mal epilepsy. When MSM was administered to patients on stable PB or primidone therapy, the mean concentrations of PB increased by statistically significant amounts of 38 and 40%, respectively. Similarly, the additional administration of MSM caused the mean concentration of PHT to rise by 78%. The data also indicate that patients with PB and/or PHT comedication have higher N-DESM-MSM serum concentrations than patients without comedication. The pharmacological reasons for these interactions are discussed. These studies demonstrate that the disturbing side effects of MSM are often due to the co-medication. A carefully planned therapeutical dose procedure with regular serum level determinations is proposed to avoid or at least reduce the adverse effects of MSM.     

Increasing Plasma Concentration Tolerability Study of Flunarizine in Comedicated Epileptic Patients

Twelve patients with intractable partial seizures [4 receiving carbamazepine (CBZ), 4 phenytoin (PHT), and 4 both] entered a study of the tolerability of flunarizine (FNR) at specified plasma concentrations. After an 8-week baseline period, a single-dose pharmacoki-netic study was performed for each patient to calculate a loading dose and maintenance dosage necessary to achieve a target plasma FNR concentration of 30 ng/ml. The first 8 patients received the loading dose (as divided doses) during a 1-week hospitalization and the maintenance dosage for the ensuing 8 weeks. These patients proceeded to treatment periods with target concentrations of 60 and then 120 ng/ml, using doses based on an assumed linear relation between dose and plasma concentration. The last 4 patients were studied only at the 120-ng/ml target level. Results indicated that this procedure successfully approximated target levels of 30 and 60 ng/ ml, but observed concentrations in the last period exceeded the 120-ng/ml target level and continued to increase with time, often necessitating a dosage reduction owing to intolerability. Calculated doses for a given target concentration varied by a factor of 12. The most frequently reported adverse experiences were sedation and increased fatigue; reports of dizziness, headache, and lethargy were also common. Based on this study, a target concentration of at least 60 but <120 ng/ml is recommended for a controlled clinical trial of the antiepileptic efficacy of FNR.     

Discontinuation of Phenytoin and Carbamazepine in Patients Receiving Felbamate

Five patients participated in a controlled discontinuation of phenytoin (PHT) and carbamazepine (CBZ) after a study in which all subjects had felbamate (FBM) added to both PHT and CBZ. Four subjects (three women and 1 man aged 23-36 years) completed the protocol. Mean total seizure frequency per day with PHT and CBZ was 1.33 +/- 0.93 (mean +/- SEM), decreasing to 0.87 +/- 0.71 with addition of FBM, and 0.82 +/- 0.78 after discontinuation of PHT. Only one subject tolerated discontinuation of CBZ; the other three had dosage reductions of 33, 54, and 63%. Toxicity attributable to FBM was not observed, and patients often described less severe seizures. Results from four refractory patients indicated that FBM was able to replace PHT and reduce the need for CBZ. In addition, as PHT dosages were reduced, FBM clearance decreased 21%. As the CBZ dosages were reduced. FBM clearance decreased an additional 16.5%.     

The Effects of Genetic Polymorphisms of CYP2C9 and CYP2C 19 on Phenytoin Metabolism in Japanese Adult Patients with Epilepsy: Studies in Stereoselective Hydroxylation and Population Pharmacokinetics

Summary: Purpose : The aim of this study was to clarify the effects of genetic polymorphisms of cytochrome P450 (CYP) 2C9 and 2C19 on the metabolism of phenytoin (PHT). In addition, a population pharmacokinetic analysis was performed.
Methods: The genotype of CYP2C9 (Arg¹⁴⁴/Cys, Ile³⁵⁹/Leu) and CYP2C19 (*1, *2 or *3) in 134 Japanese adult patients with epilepsy treated with PHT were determined, and their serum concentrations of 5-(4-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) enantiomers, being major metabolites of PHT, were measured. A population pharmacokinetic analysis (NONMEM analysis) was performed to evaluate whether genetic polymorphism of CYP2C9/19 affects the clinical use of PHT by using the 336 dose-serum concentration data.
Results: The mean maximal elimination rate (Vmax) was 42% lower in the heterozygote for Leu359 allele in CYP2C9, and the mean Michaelis-Menten constants (K,) in the heterozygous extensive metabolizers and the poor metabolizers of CYP2C19 were 22 and 54%, respectively, higher than those without the mutations in CYP2C9/19 genes. (R)- and (5')- p -HPPHPHT ratios were lower in patients with mutations in CYP2C9 or CYP2C19 gene than those in patients without mutations.
Conclusions: Although the hydroxylation capacity of PHT was impaired with mutations of CYP2C9/19, the impairment was greater for CYP2C9. In view of the clinical use of PHT, two important conclusions were derived from this population study. First, the serum PHT concentration in patients with the Leu359 allele in CYP2C9 would increase dramatically even at lower daily doses. Second, the patients with CYP2C19 mutations should be treated carefully at higher daily doses of PHT.     

Disposition of Carbamazepine and Phenytoin in Pregnancy

Summary: Free and total plasma concentrations of phenytoin (PHT) and carbamazepine (CBZ) and its active metabolite carbamazepine-10,11-epoxide (CBZ-E) were determined in a prospective study of 86 pregnant epileptic women. The pharmacokinetics of PHT and CBZ during the three trimesters were compared with kinetics at least 10 weeks postpartum. Plasma clearance and unbound CBZ clearance were slightly decreased during the last trimester. Total and free plasma CBZ-E concentrations did not change significantly during pregnancy. Plasma PHT clearance, on the other hand, increased from the first trimester. A less pronounced increase was observed for clearance of unbound PHT; the increase was statistically significant only during the third trimester.     

Pharmacokinetics and Clinical Use of Parenteral Phenytoin,Phenobarbital, and Paraldehyde

Summary: Intravenous phenytoin, phenobarbital, and paraldehyde are effective and safe for the treatment of acute seizures such as status epilepticus. All of these drugs should be infused in a diluted solution and at a slow rate to minimize the occurrence of adverse effects.     

Pharmacokinetics and Clinical Use of Parenteral Phenytoin, Phenobarbital, and Paraldehyde

Summary: Intravenous phenytoin, phenobarbital, and paraldehyde are effective and safe for the treatment of acute seizures such as status epilepticus. All of these drugs should be infused in a diluted solution and at a slow rate to minimize the occurrence of adverse effects.     

Effect of Phenytoin on Antibody Production: Use of a Murine Model

An animal model was used to study the effects of phenytoin on immune function. Inbred NFS mice, injected with phenytoin, 10-40 mg/kg, and immunized with bovine serum albumin (BSA), demonstrated a dose-dependent decrease in production of IgG antibodies to BSA. Phenytoin at the dosages used in this study did not appear to be overtly toxic to immune organs and cells as judged by normal weights of thymus and spleen and normal WBC counts of mice injected with phenytoin. In addition, mice receiving phenytoin had normal body weights, liver weights, and hematocrits. The usefulness of an animal model to study immunomodulatory effects of antiepileptic drugs is discussed.     

Discontinuation of Phenytoin, Carbamazepine, and Valproate in Patients with Active Epilepsy

The effects of discontinuing individual antiepileptic drugs (AEDs) in patients with active epilepsy who are receiving combination therapy have not been studied systematically. We report a double-blind, prospective study of discontinuation of phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA) in 70 patients with chronic active epilepsy. Each drug discontinuation was randomized to one of two relatively fast rates of reduction, and a control group of 25 patients continued with stable therapy. Patients who had CBZ removed had a significant increase in seizures that was maintained for 4 weeks after the end of drug reduction, and 10 of these 23 patients had to restart therapy with CBZ. There was no significant change in seizure numbers in the other groups. Two patients discontinued from VPA had to restart the drug; none had to restart PHT. The optimal rates of reduction of CBZ remain uncertain. There was no evidence for a clinically or temporally distinct burst of "discontinuation seizures" in any group. Any marked increase in seizures always resolved on reintroduction of the discontinued drug.     

Pharmacokinetics of Fosphenytoin in Patients with Hepatic or Renal Disease

PURPOSE: The pharmacokinetic behavior of fosphenytoin (FOS), the water-soluble prodrug of phenytoin (PHT), has been characterized in normal subjects. This is the first study of the effect of hepatic or renal disease on the rate and extent of conversion of FOS to PHT. METHODS: A single dose of fosphenytoin (250 mg over a period of 30 min) was administered to subjects with hepatic cirrhosis (n = 4), renal disease requiring maintenance hemodialysis (n = 4), and healthy controls (n = 4). Serial plasma concentrations were measured, and pharmacokinetic parameters were calculated. RESULTS: The mean time to reach the peak plasma FOS concentration was similar for each of the three groups. However, the mean time to achieve peak plasma concentrations of PHT tended to occur earlier in the hepatic or renal disease groups than in healthy subjects. The half-life of FOS was 4.5, 9.2, and 9.5 min for the three groups, respectively. There was a trend toward increased FOS clearance and earlier peak PHT concentration in subjects with hepatic or renal disease. This finding is consistent with decreased binding of FOS to plasma proteins and increased fraction of unbound FOS resulting from decreased plasma protein concentrations associated with these disease states. The conversion of FOS to PHT was equally efficient in subjects with hepatic or renal disease and healthy subjects. CONCLUSIONS: Although the differences in pharmacokinetic parameters between the three groups were not statistically significant, these data suggest the need for close clinical monitoring during FOS administration to patients with hepatic or renal disease. To minimize the incidence of adverse effects in this patient population, FOS may need to be administered at lower doses or infused more slowly.     

Effects of Ketamine Anesthesia on Phenytoin Biodisposition

After oral administration (10% suspension in arabic gum, at 500 mg/kg), total phenytoin (PHT) concentrations were measured in the blood and brain of rats anesthetized with ketamine (60 mg/kg, intraperitoneally i.p.) and in a control group that received only PHT. The concentration of PHT in blood and brain was significantly higher in the ketamine than in the control group. At 1, 1.5, 2, and 3 h, increased brain PHT reflected increased blood concentrations. At all times, the plasma protein binding of PHT was similar in both groups. After intravenous (i.v.) administration, instead, at 10 mg/kg, total PHT concentrations were similar in rats anesthetized with ketamine (60 mg/kg, i.p.) and in a control group that received only PHT under mild ether anesthesia. Thus, the main factor involved with the altered PHT biodisposition caused by ketamine anesthesia appears to be increased absorption of the drug.