Bioavailability of Phenytoin

Neuvonen, Pertti J.

doi:10.2165/00003088-197904020-00002

Cited by 59 publications

(5 citation statements)

References 9 publications

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“…In a previous bioavailability study in healthy volunteers using single doses of 600 mg phenytoin the mean area under the serum phenytoin concentration curve was 57% higher with the new Hydantin tablets than with the old tablets (Neuvonen, Pentikainen & Elfving, 1977). In the present study in epileptic outpatients there was a mean increase of about 70% in serum phenytoin concentration after the increase of bioavailability of phenytoin tablets.…”

Section: Discussionsupporting

confidence: 50%

Effect of increased bioavailability of phenytoin tablets on serum phenytoin concentration in epileptic out‐patients.

Neuvonen¹,

Bardy²,

Lehtovaara³

1979

Brit J Clinical Pharma

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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 pg/ml or less but the mean increase was 100% in patients with serum phenytoin between 5 and 10 jtg/ml. In patients with serum phenytoin concentrations more than 10 jig/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.

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Section: Discussionsupporting

confidence: 50%

Effect of increased bioavailability of phenytoin tablets on serum phenytoin concentration in epileptic out‐patients.

Neuvonen¹,

Bardy²,

Lehtovaara³

1979

Brit J Clinical Pharma

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“…4 Furthermore, only 10% of phenytoin is metabolized by CYP2C19, whereas 90% is metabolized by CYP2C9. 1,3 Therefore, the genetic polymorphism of CYP2C9 is most likely responsible for the supratherapeutic phenytoin level in this patient. Despite its modest prevalence (3%) in the Asian population, genetic analysis revealed that this patient had a homozygous CYP3A3*3 mutation, which significantly reduced the metabolism of the usual daily dose of phenytoin by more than 50%.…”

Section: Toxicology Consultantmentioning

confidence: 92%

“…Therefore, a high serum concentration will result in a greater amount of free drug in the plasma and a longer elimination half-life. [1][2][3] In general, acute overdose and drug-drug interactions are the causes of phenytoin intoxication. Due to its metabolism by CYP2C19, omeprazole had a minor interaction with phenytoin in this patient, which may have elevated phenytoin levels.…”

Section: Toxicology Consultantmentioning

confidence: 99%

Phenytoin Intoxication in a Patient Receiving a Therapeutic Dose for Postoperative Seizure Prophylaxis: A Case Study

Prasertsup,

Chomchai,

Mekavuthikul

et al. 2023

Therapeutic Drug Monitoring

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Objective: Phenytoin is commonly prescribed to prevent postoperative seizures. Despite the rarity of the CYP2C9 genetic polymorphism, which may result in poor phenytoin metabolism, in the Thai population, the authors report a case of phenytoin toxicity in a patient with poor metabolism administered with a standard dose of phenytoin. Case Report: A 58-year-old Thai woman presented to the outpatient clinic with a 2-day history of nausea, vomiting, and dizziness. She underwent craniotomy for tumor removal 2 weeks after being diagnosed with tuberculum sellae meningioma. After the surgery, she was prescribed 300 mg of phenytoin daily to prevent seizures. During the physical examination, ataxia, horizontal nystagmus, and cerebellar abnormalities were observed, with an initial serum phenytoin concentration of 58.85 mg/L. The brain imaging results were unremarkable. Omeprazole was the only recognized drug interaction; however, it is highly unlikely to account for this condition. Pharmacogenetic investigation of CYP2C9 revealed a homozygous CYP2C9*3/*3 mutation, which is indicative of suboptimal drug metabolism and can reduce phenytoin metabolism by 50%. This patient was administered repeated dosages of activated charcoal over the course of 2 days. Her symptoms eventually subsided, with the phenytoin levels dropping to 29.51 mg/L. Conclusions: In the absence of an overdose history or drug–drug interaction, CYP2C9 polymorphism should be suspected in patients with phenytoin toxicity. In such situations, the phenytoin dosage must be decreased and monitored closely.

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“…The tablets having the lowest bioavailability had by far the largest particle size. Their bioavailability did not correlate with the tablets' disintegration time, but correlated well with their in vitro dissolution rate in borate buffer . The brands having differing bioavailabilities were a real clinical challenge, particularly because of the saturation kinetics of phenytoin.…”

Section: Bioavailability Problems – Case Phenytoinmentioning

confidence: 94%

Towards Safer and More Predictable Drug Treatment – Reflections from Studies of the First BCPT Prize Awardee

Neuvonen

2012

Basic Clin Pharma Tox

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This MiniReview is a personal recollection of selected research topics, which the author in collaboration with colleagues has studied, aiming to improve the predictability of drug therapy. In early studies, we found bi-and trivalent cations to reduce the absorption of various tetracyclines and fluoroquinolones. Certain antacids elevated the bioavailability of some nonsteroidal anti-inflammatory drugs and sulphonylureas. Various brands of phenytoin tablets revealed great differences in their bioavailability, causing clinical consequences. Numerous factors affecting the antidotal effect of activated charcoal were also studied, with charcoal compared to other gastrointestinal decontamination methods, including ipecac and gastric lavage. Effect of age and diseases on the pharmacokinetics of drugs was a research topic. Acute sotalol intoxications revealed its QT-prolonging properties, and even small mixed overdoses of moclobemide with serotonergic drugs proved fatal. Itraconazole and other potent inhibitors of CYP3A4 could drastically increase exposure to drugs like midazolam, triazolam, buspirone, lovastatin, simvastatin and oxycodone, whereas rifampicin greatly reduced their plasma concentrations. A change from potent inhibition to induction caused a 400-fold change in the exposure to oral midazolam. CYP2C8 was revealed to be crucial in the metabolism and interactions of several drugs. Many interactions affecting statins are CYP3A4-mediated, but transporters are important in certain interactions. Tizanidine is very susceptible to CYP1A2 inhibition. Fruit juices such as grapefruit juice can raise or lower exposure to different drugs. Both drug interactions and pharmacogenetics can modify the activity of cell membrane transporters and cause variability in the pharmacokinetics of and response to their substrate drugs.This MiniReview is a personal recollection of certain research projects in which the author has participated in collaboration with many colleagues in the last 45 years. Without clever doctoral students and brilliant co-supervisors, many of these studies would not have been possible. I am most grateful to all these colleagues in Finland and abroad for our very smooth and fruitful cooperation. This MiniReview also reflects some of the topics that have been relevant in clinical pharmacological research during these decades. It also gives some hints as to the challenges that researchers sometimes may face if they observe adverse drug interactions or other potentially negative aspects of a drug. Interference with the Absorption Tetracyclines and FluoroquinolonesMany of the patients suffering from prolonged infections and having a subnormal haemoglobin level were, in the 1960s and early 1970s, given tetracyclines and iron. Nowadays, it is well known that infectious anaemia is not an iron-deficient anaemia and that iron administration may even have a negative effect on recovery. As there were some reports that bi-and trivalent cations could form insoluble chelates with tetracyclines, we decided to stud...

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Bioavailability of Phenytoin

Cited by 59 publications

References 9 publications

Effect of increased bioavailability of phenytoin tablets on serum phenytoin concentration in epileptic out‐patients.

Effect of increased bioavailability of phenytoin tablets on serum phenytoin concentration in epileptic out‐patients.

Phenytoin Intoxication in a Patient Receiving a Therapeutic Dose for Postoperative Seizure Prophylaxis: A Case Study

Towards Safer and More Predictable Drug Treatment – Reflections from Studies of the First BCPT Prize Awardee

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