Serum Phenytoin Research Articles

The effects of toxic and non-toxic serum phenytoin levels on carbohydrate tolerance and insulin levels.

The effect of toxic and non-toxic phenytoin levels on carobhydrate tolerance and insulin levels was studied in 18 patients with epilepsy and 17 control subjects. Toxic levels were defined as a serum level greater than 20 microgram/ml. Toxic levels occurred in 11 patients and nontoxic levels in seven patients. Blood glucose and insulin levels were measured at 30-min intervals for a period of 3 h following the ingestion of 50 g glucose. Blood glucose levels were measured by the ferricyanide method, and serum insulin levels by immunoassay of insulin with insulin antibody precipitate. Serum phenytoin levels were measured by gas liquid chromatography. The insulin profiles were the same for all three groups, but there was a significant delay in reaching peak glucose concentrations in patients with toxic levels of phenytoin. It was therefore confirmed that non-toxic levels of phenytoin do not affect carbohydrate tolerance or insulin levels when phenytoin is used in the routine treatement of epilepsy, and it has also been shown that toxic levels of phenytoin do not affect carbohydrate tolerance when the high levels are detected at an early stage.

Differences between the Measured and Calculated Free Serum Phenytoin Concentrations in Epileptic Patients

PurposeThe pharmacokinetics of phenytoin is complicated by genetic and environmental differences. It is, therefore, important to monitor the serum concentrations in patients who receive phenytoin. Because most of the phenytoin in serum is bound to proteins, the level of serum albumin influences the amount of free phenytoin.Materials and MethodsWe compared the measured and calculated free phenytoin levels in epileptic patients who were taking phenytoin monotherapy, using the Sheiner-Tozer equation. A total of 49 patients (30 men and 19 women; age range, 15 - 87 years) were included in the study and their trough serum phenytoin and albumin concentrations were analyzed.ResultsThe linear correlation between free and total phenytoin concentrations was moderate (r = 0.822, p < 0.001). The mean difference between measured and calculated free phenytoin was large (0.65 ± 0.88 µg/mL; 95% confidence interval (CI), -1.11 to 2.41). After dividing the patients into groups by albumin concentration, hypoalbuminemic patients (< 3.5 g/dL) more often had a greater percent difference (≥ 20%) than observed in the normoalbuminemic (≥ 3.5 g/dL) group.ConclusionIn hypoalbuminemic patients, the measurement of free phenytoin level is necessary to properly evaluate the phenytoin level than that calculated from total phenytoin level.

Life-threatening cardiotoxicity due to chronic oral phenytoin overdose

Severe cardiac adverse effects are often related to intravenous phenytoin overdose. However, there is no reported cardiotoxicity resulting from oral overdose of phenytoin. We report a patient with post-traumatic epilepsy who received oral phenytoin for five months and developed life-threatening junctional bradycardia, with his serum phenytoin level reaching up to 91 microg/mL. The patient was successfully treated with temporary transvenous pacemaker implantation for his severe bradycardia and hypotension. To our knowledge, our patient had the most serious cardiovascular toxicity ever reported with chronic oral phenytoin overdose. From emergency department (ED) physician's perspective, when a patient with dysrhythmias and cardiovascular collapse is presented to the ED, severe phenytoin overdose should be considered in patients on oral phenytoin with hyperbilirubinemia, hypoalbuminemia, and severe electrolyte imbalance.

Phenytoin Metabolite Renal Calculus: An Index Case

Drugs and their metabolites are known factors in 1% to 2% of all kidney stones. Certain antiepileptic drugs are known to cause stone formation. Phenytoin is used as a first line antiepileptic therapy for many seizure disorders. We present what we believe to be the first report of a phenytoin metabolite urinary stone. A 79-year-old woman with a fever and seizure disorder was found to have a right pelvic kidney with hydronephrosis and multiple large calcifications. She had been taking the antiepileptic medication phenytoin for the past 10 years. Average total serum phenytoin level from the year prior was in the normal range. Free phenytoin levels were not routinely monitored, but the one value available was elevated at 5.1 ng/dL. The patient underwent a percutaneous nephrolitomy, ultimately expiring from medical complications after the procedure. Final stone analysis revealed a composition of 35% phenytoin metabolite (5-(para-hydroxyphenyl)-5-phenylhydantoin) and 65% proteinaceous material. An extensive review of literature including PubMed, MedLine, and various internet search engines was performed, searching for any prior reports of urinary calculi formed from phenytoin or its metabolite. No previous reports of phenytoin or phenytoin metabolite urinary stones were found in the medical literature. Phenytoin has many known ill effects on the genitourinary system including acute interstitial nephritis, nephrotic syndrome, acute renal failure, and priapism. Now we can add urinary lithiasis to the list of its potential adverse effects. This article represents the first report of a phenytoin metabolite urinary stone. A metabolite of the commonly used antiepileptic medication phenytoin can cause clinically relevant urolithiasis leading to significant morbidity and even mortality. Clinicians should have an increased level of suspicion for metabolite stone formation in symptomatic patients taking antiepileptic medications. Further studies on phenytoin metabolism and its potential for inducing urinary lithiasis should be performed.

Variability of serum phenytoin levels in critically ill head injured patients in intensive care unit

Patients with large variations in phenytoin levels despite standard doses may prove to become difficult clinical problems. Our study of 34 head injury patients whose serum phenytoin levels were measured on day one and day five following intravenous loading and maintenance dose of phenytoin, showed 38.24% patients, to have therapeutic phenytoin levels on day one, while 20% were in toxic range. On day five, 23% patients were in toxic and 29.41% were in therapeutic range. Only 21% patients remained in the therapeutic range during the monitoring period. This study shows that there is a wide variability of phenytoin levels in the ICU patients with a difference of more than 100% between the highest and lowest phenytoin level in individual cases (in four patients the difference exceeded 500%) raising concern about the safety of the drug. Hence it is recommended that intensive care unit patients receiving phenytoin therapy should have periodic serum phenytoin obtained even in absence of seizures or classic signs phenytoin toxicity.

Undetectable phenytoin serum levels by an automated particle-enhanced turbidimetric inhibition immunoassay in a patient with monoclonal IgMλ

IntroductionPhenytoin is a drug used for the treatment of different types of seizures. Its variable pharmacokinetics, mainly a consequence of variable bioavailability, saturable protein binding and saturable hepatic metabolism, predisposes the drug to therapeutic drug monitoring. Several methods to analyze the drug in serum exist with immunoassays being the method of choice for routine measurements. Immunoassays are specific and sensitive, but cross-reactivity, possibly leading to erroneous serum levels, is a concern. We report a patient with falsely undetectable phenytoin serum levels. Case reportThis 73-year old woman was treated with intravenous phenytoin due to epilepsia partialis continua in the context of a bilateral cerebrovascular insult. Anamnestically, a chronic lymphatic leukemia was known. In this patient, serum phenytoin levels became only detectable by the particle enhanced turbidimetric inhibition immunoassay used after precipitation of serum proteins. Protein electrophoresis revealed a monoclonal immunoglobulin, identified as IgMλ. With other methods such as HPLC and fluorescence depolarization immunoassay, phenytoin was detectable. ConclusionWe propose interference between the monoclonal IgMλ and/or other serum proteins and the particle-enhanced turbidimetric inhibition immunoassay, rendering phenytoin falsely undetectable in samples of this patient. In such patients, alternative methods such as HPLC should be used to prevent dosage errors.

The first case of phenytoin intoxication associated with the concomitant use of phenytoin and TS-1, a combination preparation of tegafur, gimeracil, and oteracil potassium

We reported the first case of phenytoin intoxication due to the concomitant use of phenytoin and TS-1, together with a review of the literature regarding the occurrence of phenytoin intoxication due to the concomitant use of phenytoin and fluoropyrimidine antitumor drugs such as fluorouracil (5-FU) and tegafur (FT). We showed the clinical course of our patient. Reports of phenytoin intoxication due to the concomitant use of phenytoin and fluoropyrimidine antitumor drugs in the English and Japanese language literature up to 2007 were identified by searching Medline and ICHUSHI Web (Japana Centra Revuo Medicina). A patient taking phenytoin and TS-1, a combination preparation of tegafur, gimeracil, and oteracil potassium, experienced lightheadedness and repeated falls associated with an increase in serum phenytoin concentration (32.8 mug/ml) at 1 month after the start of TS-1 treatment. The time lag between initiation of combined treatment and onset of adverse symptoms suggests the presence of an indirect mechanism, rather than direct inhibition of drug-metabolizing enzymes by drugs in TS-1 or their active metabolites. Plasma phenytoin concentration should be closely monitored in patients receiving TS-1 and phenytoin concomitantly.

Statins and phenytoin interact – a case history

Statins and phenytoin interact – a case history

Steady-State Serum Phenytoin Concentrations After Nasogastric Tube Administration of Immediate-Release Phenytoin Tablets and Extended-Release Phenytoin Capsules: An Open-Label, Crossover, Clinical Trial

Background: When phenytoin is prescribed for administration via nasogastric tube, immediate-release OR) phenytoin tablets are crushed before use and extended-release (ER) phenytoin capsules are opened and only the granules are used. However, it is unknown whether the same dose of these 2 different formulations will result in the same steady-state serum phenytoin concentration. Objective: The aim of this study was to determine whether ER phenytoin capsules can be used interchangeably with IR phenytoin tablets for prophylaxis of posttraumatic seizures. Methods: Inpatients at the neurosurgical ward at Prasat Neurological Institute, Bangkok, Thailand, between October 2004 and October 2005 were enrolled in the study. All patients were initially prescribed IR phenytoin tablets 300 mg/d as a maintenance dose for prophylaxis of posttraumatic seizures. The serum phenytoin concentration was measured after ≥5 days of treatment with IR phenytoin tablets 300 mg/d (two 50-mg tablets every 8 hours) that had been crushed before being administered concomitantly with a blenderized diet through the nasogastric tube. Without a washout period, the dosage form was changed to ER phenytoin capsules (three 100-mg capsules QD). The capsules were opened and the contents were administered concomitantly with the blenderized diet through the nasogastric tube for ≥5 days. The serum phenytoin concentration was again determined. The patients were closely monitored for seizures and adverse events (AEs). Results: Thirty-three patients enrolled in the study and 17 (10 women, 7 men; mean [SD] age, 62.94 [15.94] years [range, 18-89 years]) completed the study. The mean (SD) serum phenytoin concentrations after administration of phenytoin tablets and capsules were 6.03 (5.92) μg/mL and 3.80 (2.71) μg/mL, respectively ( P = 0.019). The mean serum phenytoin concentrations, adjusted for low serum albumin concentrations after administration of tablets and capsules, were calculated and reported to be 10.33 (11.60) μg/mL and 6.28 (4.76) μg/mL, respectively ( P = 0.035). The maximum phenytoin metabolic rate (V max) (assuming the substrate concentration at which the rate of metabolism is one half V max = 4 mg/L) after the administration of phenytoin tablets and capsules was 8.37 (2.42) mg/kg · d -1 and 10.38 (6.48) mg/kg · d -1, respectively. These values were not significantly different. All patients were seizure-free and no AEs were observed. Conclusion: The steady-state serum phenytoin concentration was significantly lower with ER phenytoin capsules 300 mg/d than IR phenytoin tablets 300 mg/d administered via nasogastric feeding tube concomitantly administered with a blenderized diet in these neurosurgical patients. Key words: phenytoin nasogastric tube feeding extended-release capsule immediate-release tablet

Contributions of CYP2C9/CYP2C19 Genotypes and Drug Interaction to the Phenytoin Treatment in the Korean Epileptic Patients in the Clinical Setting

We examined the contribution of CYP2C9 and CYP2C19 genotypes and drug interactions to the phenytoin metabolism among 97 Korean epileptic patients to determine if pharmacogenetic testing could be utilized in routine clinical practice. The CYP2C9 polymorphism is a wellknown major genetic factor responsible for phenytoin metabolism. The CYP219 polymorphism, with a high incidence of variant alleles, has a minor influence on phenytoin treated Koran patients. Using a multiple regression model for evaluation of the CYP2C9 and CYP2C19 genotypes, together with other non-genetic variables, we explained 39.6% of the variance in serum phenytoin levels. Incorporation of genotyping for CYP2C9 and CYP2C19 into a clinical practice may be of some help in the determination of phenytoin dosage. However, because concurrent drug treatment is common in patients taking phenytoin and many environmental factors are likely to play a role in drug metabolism, these factors may overwhelm the relevance of CYP polymorphisms in the clinical setting. Further investigations with an approach to dose assessment that includes comprehensive interpretation of both pharmacogenetic and pharmacokinetic data along with understanding of the mechanism of drug interactions in dosage adjustment is warranted.

Topical phenytoin solution for treating pressure ulcers: a prospective, randomized, double-blind clinical trial

Prospective, randomized, double-blind clinical trial. To evaluate the efficacy of topical phenytoin solution in treating pressure ulcers among patients with spinal cord disorders and to evaluate the systemic absorption of topical phenytoin. Physical Medicine and Rehabilitation Unit, Christian Medical College, Vellore, India. Twenty-eight patients with stage 2 pressure ulcers were randomized to receive either phenytoin solution (5 mg/ml) or normal saline dressing on their ulcers once daily for 15 days. Efficacy of the treatment was determined by assessing the reduction in Pressure Ulcer Scores for Healing (PUSH 3.0), ulcer volume and ulcer size as on day 16. Serum phenytoin concentrations were estimated to determine the systemic absorption of topical phenytoin. Statistically insignificant but marginally higher reduction in PUSH 3.0 scores and ulcer size were seen with topical phenytoin treatment. Systemic absorption of topical phenytoin was negligible. No adverse drug events were detected during the study. Phenytoin solution is a safe topical agent that accelerates healing of pressure ulcers. However, its efficacy is only slightly more than normal saline treatment.

Complex Interactions of Drugs, Nutrients

Complex Interactions of Drugs, Nutrients

Analysis of Free Drug Fractions Using Near-Infrared Fluorescent Labels and an Ultrafast Immunoextraction/Displacement Assay

A chromatographic method was developed for measuring free drug fractions based on the use of an ultrafast immunoextraction/displacement assay (UFIDA) with near-infrared (NIR) fluorescent labels. This approach was evaluated by using it to determine the free fraction of phenytoin in serum or samples containing the binding protein human serum albumin (HSA). Items considered in the design of this method included the dissociation rate of HSA-bound phenytoin, the rate of capture of free phenytoin by immunoextraction microcolumns, the behavior of NIR fluorescent labels in a displacement format, and the overall response and stability of the resulting assay. In the final UFIDA method, the free fraction of phenytoin was extracted in approximately 100 ms by a microcolumn containing a small layer of anti-phenytoin antibodies. This gave a displacement peak for a NIR-fluorescent-labeled analogue of phenytoin that appeared within 2-3 min of sample injection, creating a signal proportional to the amount of free phenytoin in the sample. The UFIDA method provided results within 1-5% of those determined by ultrafiltration for reference samples. The lower limit of detection was 570 pM, and the linear range extended up to 10 microM. This approach is not limited to phenytoin but can be adapted for other analytes through the use of appropriate antibodies and labeled analogues.

Interpretation of serum phenytoin concentrations: Who would have thought that preventing and treating seizures were this challenging?*

Division of Critical Care Medicine and Department of Neurology, Children's National Medical Center, Washington, DC *See also p. 434.

Effect of CYP2C19 genetic polymorphism on pharmacokinetics of phenytoin and phenobarbital in Japanese epileptic patients using Non-linear Mixed Effects Model approach

To clarify the effect of genetic polymorphism of CYP2C19 on pharmacokinetics of phenytoin and phenobarbital using a Non-linear Mixed Effects Modelling analysis in Japanese epileptic patients. A total of 326 serum phenytoin concentrations were collected from 132 patients, and a total of 144 serum phenobarbital concentrations were collected from 74 patients during their clinical routine care. The maximal elimination rate of phenytoin decreased by 10.2% in patients with CYP2C19*1/*2 compared with patients with normal CYP2C19. The Michaelis-Menten constants in the patients with CYP2C19*1/*3 and the poor metabolizers of (CYP2C19*2/*2 or *2/*3 or *3/*3) were 27% and 54% higher than those for the patients with normal CYP2C19, respectively. The total body clearance of phenobarbital decreased by 19.3% in patients with CYP2C19*1/*3 or the poor metabolizers of CYP2C19 compared with patients with normal CYP2C19 or with CYP2C19*1/*2. These findings indicated that the genetic polymorphisms of CYP2C19 contribute to the pharmacokinetic variability of phenytoin and phenobarbital, the poor metabolizers of CYP2C19, which are relatively common in Asian groups.

Acute phenytoin toxicity mimicking stroke following cardiopulmonary bypass

A 55-year-old diabetic, hypertensive and dyslipidemic male with functional class III angina was admitted for coronary revascularization. Patient had a history of stroke with left hemiparesis five years ago, with complete recovery within a year. He had one episode of seizure three years back but did not seek any medical advice. Cardiac evaluation revealed triple vessel disease with fair left ventricular function without any intracardiac clots. Liver function test revealed SGOT of 48 u/L and SGPT of 56 u/L (normal range up to 40 u/l). Ultrasonography of abdomen showed fatty liver. Carotid artery duplex scanning showed 30% stenosis of right and 45% stenosis of left internal carotid artery. Computerised tomography (CT) of brain revealed chronic infarct in right frontal and gangliocapsular region. Electroencephalogram three weeks prior to surgery showed a spike and wave discharge over temporal areas consistent with seizure disorder, and patient was started on oral Phenytoin 100 mg thrice daily. He underwent coronary artery bypass grafting under CPB. Postoperatively hemodynamics remained stable. Oral aspirin and Phenytoin were restarted on first postoperative day. He was initially in a state of confusion, and, on the 3rd postoperative day, developed pronounced ataxia, nystagmus, dysarthria and vomiting. A likely clinical diagnosis of posterior circulation stroke was considered. CT scan ruled out a hemorrhagic stroke but could not rule out new embolic phenomena. Heparin infusion was thus started empirically. The neurological status was slowly deteriorating. MRI done on the fifth postoperative day revealed no fresh structural lesions in the brain. At this stage a likely possibility of Phenytoin toxicity was considered. Serum total Phenytoin concentration estimation revealed a toxic level of 40 microgram/ deciliter. (Therapeutic range 10-20 mcg/dl) which clinched the diagnosis. Patient also had hyponatremia requiring frequent corrections, however levels of urinary sodium were low. Phenytoin was stopped and patient showed good recovery with no residual neurological deficit within 15 days. At discharge his serum Phenytoin level was within normal range and he was advised to remain under a neurologist follow up.

Effect of Ultrafiltrate Volume on Determination of Free Phenytoin Concentration

Monitoring free phenytoin concentration is clinically useful for patients with uremia, hepatic disease, hypoalbuminemia, and related conditions. Free phenytoin is commonly measured by immunoassay in the protein-free ultrafiltrate prepared by centrifuging serum for 20-30 minutes, using an appropriate ultrafiltration device. We studied the effect of centrifugation time (15-40 minutes) and protein concentrations on ultrafiltration volume, and the related effects on measured free phenytoin concentrations. Temperature was ambient for all studies. The ultrafiltration volumes were directly proportional to centrifugation time and were inversely proportional to the protein concentrations. Although ultrafiltration volume significantly increased with longer centrifugation time, the measured free phenytoin concentrations did not increase proportionately. The concentration of phenytoin in the residual serum retained in the ultrafiltration device did not change proportionally either. Therefore, equilibrium of phenytoin concentrations between the ultrafiltrate and retentate was maintained, regardless of centrifugation time or protein concentration.

Seizures following reduction in phenytoin level after orally administered folic acid

Phenytoin reduces folate levels and may be responsible for the development of a macrocytic anemia. This may be avoided by prophylactic administration of folic acid to patients with seizure who will be on long-term anticonvulsant treatment. The relationship between folate and phenytoin metabolism, however, is a dual and interdependent one and the addition of folic acid to a stable anticonvulsant regimen predictably lowers serum phenytoin levels.1 We report a case of recurrent seizures in a patient after the addition of folic acid for treatment of macrocytic anemia. The reduction in drug levels was substantial and resulted in several seizures in a patient previously well controlled. A 52-year-old man was admitted to the hospital for repair of an acute hip fracture. There was a history of cerebrovascular disease complicated by stroke, hemiparesis, and generalized tonic-clonic seizures. He had been free of seizures for the 3 years previous to …

Simultaneous determination of lamotrigine, phenobarbitone, carbamazepine and phenytoin in human serum by high-performance liquid chromatography

A simple reversed-phase high-performance liquid chromatography (HPLC) method was developed for the simultaneous estimation of the antiepileptic drugs (AEDs) lamotrigine (LTG), phenobarbitone (PB), carbamazepine (CBZ) and phenytoin (PHT) in human serum. The procedure involves extraction of the AEDs by mixing 200 μl of serum with 200 μl of acetonitrile containing 10 μg/ml of pentobarbitone as internal standard (IS). After centrifugation, 10 μl of the supernatant was injected onto a NOVA PAK C-18 column (250 mm × 4.6 mm, 5 μm Hypersil ODS) and eluted with a mobile phase consisting of phosphate buffer (10 mM)–methanol–acetonitrile–acetone in the ratio of 55:22:12:11 (v/v) adjusted to pH 7.0. A UV detector set at 210 nm was employed for detection. The AEDs were well resolved from the human serum constituents and the internal standard. The method can quantify LTG, PB, CBZ, and PHT at concentrations as low as 0.2 μg/ml. The method was quantitatively evaluated in terms of linearity, accuracy, precision, recovery, selectivity, sensitivity, and specificity. The method is simple, convenient, and suitable for the analysis of AEDs from human serum.

Vitamins for epilepsy

Vitamins have been reported to be effective in controlling certain types of seizures and to prevent some of the harmful effects of antiepileptic drugs (AEDs). In this review we will summarize evidence from randomized controlled trials. To assess if vitamins improve seizure control, reduce adverse effects of AEDs or improve the quality of life in people with epilepsy. We searched MEDLINE from 1966 to 2004, the Cochrane Epilepsy Group trials register (December 2004), CENTRAL (the Cochrane Controlled Trials Register) (TheCochraneLibrary Issue 4, 2004), and cross-references from identified studies. Randomized or quasi-randomized studies investigating the effects of one or more vitamins given alone or in addition to AEDs to people of any age with any type of epilepsy. Both reviewers assessed the trials for inclusion and extracted the data. Outcomes assessed included seizure frequency, gingival hyperplasia, neuropathy, changes in bone mineral content, serum calcium, alkaline phosphatase, hemogram, serum levels of AEDs, neuropsychological and quality of life outcomes. Primary analyses were by intention to treat. Fifteen studies met our inclusion criteria and were of poor methodological quality. None described randomization methods and most enrolled small numbers of participants. Nine studies (331 participants) investigated folic acid. Two studies (75 participants) found no effect for the outcome 50% or greater reduction in seizure frequency (OR 0.96; 95% CI 0.32 to 2.29). Also, no evidence was found for an effect on gingival health, intelligence, behavior, mental health or personality, or measures of red blood volume and hemoglobin content. Folic acid was not associated with any consistent changes in serum phenytoin or phenobarbitone levels or improvement in the mean motor conduction velocities of peripheral nerves. One small study (72 participants) found that thiamine improves neuropsychological functions related to psychomotor speed, visuospatial abilities, selective attention and verbal abstracting ability. One study (226 participants) found a significantly higher bone mineral content (BMC) among patients with epilepsy taking AEDs with vitamin D supplementation compared to controls who were not given supplementation (OR 3.6; 95% CI 2.48 to 4.72; p < 0.00001). The studies found no significant effects on serum calcium, alkaline phosphatase or general well-being. One small study (24 participants) found a significant decrease in seizure frequency in those treated with vitamin E compared to placebo (p = 0.00005; Peto OR 26.73; 95% CI 5.46 to 130.92). In view of methodological deficiencies and limited number of individual studies, we have found no reliable evidence to support the routine use of vitamins in patients with epilepsy. Further trials are needed, especially to assess the utility of vitamin D supplementation to prevent osteomalacia and the role of vitamin E on seizures and thiamine in improving cognitive functions.