• Molecular & Cellular Toxicology
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• v.2 no.4
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• pp.262-265
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• 2006

We report a case of phenytoin toxicity due to impaired drug metabolism in a patient homozygous for $CYP2C9^{\ast}3$. A 46-year-old woman was taking phenytoin to prevent postoperative seizures. She attained high serum phenytoin levels at the standard doses (300 mg/day) and developed symptoms of phenytoin toxicity including blurred vision, nausea and headache. The patient was treated with reduced doses of phenytoin and then phenytoin therapy was finally discontinued. Genotyping for CYP2C9 revealed that this patient had a homozygous genotype, $CYP2C9^{\ast}3/^{\ast}3$. This is the first Korean case of phenytoin toxicity with homozygous $CYP2C9^{\ast}3$. This case suggests the clinical usefulness of pharmacogenetic testing for individualized dosage adjustments of phenytoin.

• The Korean Journal of Pharmacology
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• v.18 no.2
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• pp.51-58
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• 1982

In this paper, the influence of phenytoin and phenobarbical on the changes of brain norepinephrine(NE) content, plasma corticosterone and blood sugar level in mice were studied. The results obtained were summarized as follows: 1) Phenytoin(50 mg/kg) increased the brain NE content but phenobarbital(50 mg/kg) did not affect. The increase of the brain NE content induced phenytoin was potentiated by phenobarbital pretreatment. 2) Phenytoin(25 mg/kg, 50 mg/kg) markedly increased the level of plasma corticosterone but phenobarbital did not affect. The increase of the plasma corticosterone induced by phenytoin was inhibited by phenobarbital pretreatment. 3) Phenytoin(50 mg/kg) markedly increased the blood sugar level but phenobarbital did not affect. The increase of the blood sugar induced by phenytoin was not affected by phenobarbital pretreatment.

• Archives of Pharmacal Research
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• v.20 no.5
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• pp.480-485
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• 1997

The absorption profile of phenytoin Na emulsion were examined compared to that of phenytoin suspension after oral administration in the rat. The corn oil-in-water emulsion, particle size of $184{\pm}$57.8 nm, was prepared using a microfludizer, and phenytoin Na added by shaft homogenizer. The phenytoin emulsion or suspension, 100 mg/kg, were intubated intragastrically using oral dosing needle and blood samples were withdrawn via an indwelling cannula from the conscious rat. Plasma concentrations of phenytoin were measured with HPLC using phenacetin as an internal standard. The plasma concentration versus time data were fitted to a one compartment open model and the pharmacokinetic parameters were calculated using the computer program, Boomer. The phenytoin plasma concentrations from the emulsion at each observed time were about 1.5-2 times higher than those from the suspension, significantly at time of 5, 6 and 7 hr after administration. The absorption $(k_a)$ and elimination rate constant $(k_e)$ were not altered significantly, however the AUC increased from 65.6 to $106.7{\mu}ghr/ml$ after phenytoin suspension or emulsion oral administration, respectively. From an equilibrium dialysis study, the diffusion rate constant $(k_{IE})$ was considerably higher from the phenytoin Na emulsion $(0.0439 hr{-1})$ than phenytoin suspension $(0.0014 hr{-1})$.

• YAKHAK HOEJI
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• v.30 no.1
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• pp.14-23
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• 1986

This study was conducted to investigate the correlation between the dissolution rates and the bioavailabilities of commercial phenytoin products, and also the correlation between their biovailabilities in rabbits and those in humans. Dissolution test was conducted in pH 9. 0 alkaline borate buffer (0.2M) using basket method with seven phenytoin products commercially available. According to the dissolution rate, the phenytoin products were divided into three groups, such as rapid, intermediate and slow group. Three phenytoin products from each group were selected for the bioavailability test in rabbits and humans. The bioavailability test was carried out in rabbits and normal volunteers using cross over design. Single doses of 20mg/kg and 300mg/man were orally administered to rabbits and normal volunteers respectively. Average $C_{max}$, $t_{max}$ and AUC of three phenytoin products were determined from the serum concentration-time curve in rabbit and human experiments. The relative bioavailability evaluation was conducted using AUC of three phenytoin products. The correlations between the dissolution rate constants and bioavailabilities (AUC) of three phenytoin products in rabbits as well as those in humans were not found. Whereas, there was significant correlation between average AUC of three phenytoin products in humans and those in rabbits (r=0.993, p<0.1). From the results of this experiment, it can be concluded that the bioavailability of phenytoin products in humans may be predicted from the results of the rabbit experiment. Also it is assumed that the prediction of the bioavailability of phenytoin products in humans may be difficult from the only results of in vitro dissolution test.

• Journal of Periodontal and Implant Science
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• v.24 no.1
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• pp.98-108
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• 1994

Gingival hyperplasia is frequently associated with the long-term use of phenytoin for control of convulsive disorder. The purpose of this study was to investigate on the effects of lipopolysaccharides (LPS), ursolic acid and oleanolic acid to phenytoin-induced cell activity in human gingival fibroblast. Human gingival fibroblasts were cultured form the healthy gingiva of orthodontic patients. Gingival fibroblasts were trypsinized and transferred to the weels of microtest plates. Fibroblast were cultured in growth medium added $5{\mu}g/ml$ of phenytoin, $5{\mu}g/ml$ of LPS, $10^{-7}M$ of ursolic acid and oleanolic acid. The passage number of cultured fibroblasts were fifth and eight. Cell morphology was examined by inverted microscope and the cell activity was measured by proliferation assay. Ursolic acid significantly modulated cell morphology into globular shape at the concentrantion of $10^{-7}M$ in the presence of phenytoin and LPS, and the cell activity was significantl decreased by ursolic acid or oleanolic acid regardless of the presence of phenytoin and LPS. These results suggested that the increased phenytoin-induced cell activity might be modulated by ursolic acid regardless of the presence of phenytoin and LPS. These results suggested that the increased phenytoin-induced cell activity might be modulated by ursolic acid or oleanolic acid. Further study is needed to clarify their toxicological effects on cellular modulation and mRNA expression change.

• Journal of Pharmaceutical Investigation
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• v.24 no.4
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• pp.289-295
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• 1994

Pharmacokinetic drug interaction between phenytoin and verapamil was investigated following i.v. administration of two drugs concomitantly to rabbits. Verapamil was coadministered with phenytoin (5 mg/kg) to rabbits at the doses of 0.5,1 and 2 mg/kg, respectively. Plasma concentration and AUC of phenytoin were increased significantly, but volume of distribution and total body clearance were decreased significantly (p<0.05) at doses of 1mg and 2mg/kg of verapamil, respectively. From the results of this experiment, it is desirable that dosage regimen of phenytoin should be adjusted and that therapeutic drug monitoring should be performed for reduction of side or toxic effect when phenytoin should be administered with verapamil in clinical practice.

• Journal of Pharmaceutical Investigation
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• v.26 no.2
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• pp.113-117
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• 1996

This study was attempted to investigate the pharmacokinetic interaction between sodium valproate (4, 8, 16 mg/kg, i.v.) and phenytoin (4 mg/kg, i.v.) in rabbits. The plasma concentration and area under the curve (AUC) of phenytoin were increased significantly (p<0.05, p<0.01) when coadministered with sodium valproate (4, 8, 16 mg/kg) in rabbits. The volume or distribution and total body clearance of phenytoin were decreased significantly (p<0.05, p<0.01) when coadministered with sodium valproate (8, 16 mg/kg) in rabbit. From the results of this experiment, it is desirable that dosage regimen of phenytoin should be adjusted and therapeutic drug monitoring should be performed for reduction of side or toxic effect when phenytoin will be coadministered with sodium valproate in clinical use.

• Journal of Pharmaceutical Investigation
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• v.23 no.1
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• pp.27-32
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• 1993

Pharmacokinetic drug interaction between phenytoin and diltiazem was investigated following i.v. administration concomitantly to rabbits. Diltiazem was coadministered at doses of 1, 2 and 3 mg/kg, respectively, with phenytoin (5 mg/kg) to rabbits. Plasma concentration and AUC of phenytoin were increased significantly, but volume of distribution and total body clearance were decreased significantly (p<0.05) at doses of 2 mg and 3 mg/kg of diltiazem. From the results of this experiment, it is desirable that dosage regimen of phenytoin should be adjusted and that therapeutic drug monitoring should be practiced for reduction of side or toxic effect when phenytoin should be administered with diltiazem in clinical practice.

• Proceedings of the Korea Contents Association Conference
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• 2016.05a
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• pp.433-434
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• 2016

Cerebellar atrophy was found that a patient was taking oral phenytoin for 3 years. 53 years old female patient with General tonic clonic(GTC) type seizure was prescribed phenytoin. In the process, she developed ataxic gate, dysarthria. Brain magnetic resonance imaging(MRI) finding was revealed differential diagnosis cerebellar atrophy. She was prescribed epileptol instead of phenytoin. But leukopenia, thrombocytopenia occurred. As a result, phenytoin restarted. Development of medical state decreased abuse of anticonvulsants. Considering various convulsive disorders, we must give attention to using anticonvulsants.

• Journal of Korean Neurosurgical Society
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• v.58 no.2
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• pp.163-166
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• 2015

The prophylactic use of phenytoin during and after brain surgery and cranial irradiation is a common measure in brain tumor therapy. Phenytoin has been associated with variety of adverse skin reactions including urticaria, erythroderma, erythema multiforme (EM), Stevens-Johnson syndrome, and toxic epidermal necrolysis. EM associated with phenytoin and cranial radiation therapy (EMPACT) is a rare specific entity among patients with brain tumors receiving radiation therapy while on prophylactic anti-convulsive therapy. Herein we report a 41-year-old female patient with left temporal glial tumor who underwent surgery and then received whole brain radiation therapy and chemotherapy. After 24 days of continous prophylactic phenytoin therapy the patient developed minor skin reactions and 2 days later the patient returned with generalized erythamatous and itchy maculopapuler rash involving neck, chest, face, trunk, extremities. There was significant periorbital and perioral edema. Painful mucosal lesions consisting of oral and platal erosions also occurred and prevented oral intake significantly. Phenytoin was discontinued gradually. Systemic admistration of corticosteroids combined with topical usage of steroids for oral lesions resulted in complete resolution of eruptions in 3 weeks. All cutaneous lesions in patients with phenytoin usage with the radiotherapy must be evoluated with suspicion for EM.