Dose Of Phenytoin Research Articles

Influence of CYP2C9 phenotypes on phenytoin plasma concentration in neurosurgical Brazilian patients.

To investigate the association of CYP2C9 metabolic phenotypes with phenytoin plasma concentration ([PTH]) in neurosurgical patients from the Brazilian Public Health System. Patients (n = 170) were treated with phenytoin (300 mg/day) perioperatively as prophylaxis for postoperative seizures. Two to 10 days after surgery, a blood sample was collected for quantification of [PTH] and genotyping of CYP2C9*2 and *3 alleles. CYP2C9 metabolic phenotypes, NM (normal), IM (intermediate), and PM (poor) metabolizer, were inferred from CYP2C9 diplotypes. Linear regression modeling was applied to identify predictors of [PTH]. Wide (22-fold) interindividual variation in [PTH] was observed (2.2-47.5 mg/l). [PTH] associated significantly (Kruskal-Wallis P < 0.005) with CYP2C9 phenotypes and there was a significant trend (Jonckheere-Terpstra test, P < 0.0001) for [PTH] increase in the order NM < IM < PM. [PTH] was within the target therapeutic range (10-20 mg/l) in 34.7% of patients, while 39.4% and 25.9% had [PTH] below and above the range, respectively. CYP2C9 phenotypes associated significantly (chi-square P = 0.004) with the distribution of patients in [PHT] therapeutic categories and the Cramér's V test pointed to moderate magnitude of the effect of CYP2C9 phenotypes (V = 0.211). Diplotype-predicted CYP2C9 metabolic phenotypes are associated significantly with [PTH] in neurosurgical Brazilian patients receiving phenytoin for postsurgery seizure prophylaxis. [PHT] increased progressively in the phenotype order NM < IM < PM, and all PM patients had [PHT] above the target therapeutic range, consistent with the CPIC guideline 'strong' recommendation for phenytoin dosing adjustments in PMs.

Patient resuscitated after cardiopulmonary arrest exhibits abnormally increased phenytoin metabolic rate due to unknown factors: a case report

BackgroundFosphenytoin (FOS) is a prodrug of phenytoin (PHT) with a metabolism that exhibits Michaelis–Menten-type kinetics. Genetic polymorphisms of the metabolic enzymes of PHT make it challenging to predict its plasma concentrations. High plasma PHT concentrations are typically problematic, and several causes have been elucidated. In contrast, cases of patients with low PHT plasma concentrations that did not increase despite the administration of appropriate PHT doses have been reported, and the causes may include changes in plasma protein-binding rates, genetic mutations, and concomitant use of drugs that induce liver enzymes; however, even these factors do not explain the low PHT plasma concentrations in some cases.Case presentationWe encountered the case of a patient with plasma PHT concentrations that were continuously < 0.7 µg/mL after daily use of FOS for seizures that occurred after cardiopulmonary arrest. We analyzed the protein-unbound fraction, urinary metabolites, and related genes to investigate the cause. False negatives due to the measurement method, errors in dosage and administration method, and increased excretion of PHT were excluded. Hepatic metabolic activity of PHT increased to 4.6–6.1 times the normal level. The S/R ratio of 5-(p-hydroxyphenyl)-5-phenylhydantoin-glucuronide, a major PHT metabolite, was normal at 15.2, suggesting increased activities of CYP2C9 and CYP2C19. Furthermore, the protein-unbound fraction of PHT was 5.2–6.9%, CYP2C19*17 was wild type, and there was no concomitant drug use to induce both enzymes.ConclusionsThe low PHT plasma concentration in this patient was found to be caused by increased hepatic metabolic activity that could not be explained by known factors. Careful monitoring is necessary to consider the possibility of increased hepatic metabolic activity in similar cases.

To Study Perioperative Changes in Plasma Phenytoin Levels in Patients with Brain Tumor Undergoing Craniotomy and Its Correlation with Postoperative Seizures

Abstract Introduction Phenytoin, although commonly used for postoperative seizure prophylaxis, exhibits variable results in mitigating seizure frequency following craniotomy. These discrepancies may be linked to a reduction in plasma phenytoin levels subsequent to the surgical intervention. Aims This prospective study aims to characterize changes in plasma phenytoin levels after craniotomy and their relationship with intraoperative blood loss. Methods Fifty consecutive patients were enrolled in this study after obtaining written informed consent. These patients had either been on oral phenytoin for at least 7 days or had received an intravenous loading dose before undergoing craniotomy. Serum phenytoin levels were measured 24 hours preoperatively, immediately before craniotomy (prior to skin incision), postcraniotomy (after skin closure), and 24 hours postcraniotomy. Additionally, intraoperative blood loss was calculated using a modified Gross formula. Results Immediately following craniotomy, there was a statistically significant mean decline of 28.16% in serum phenytoin levels. Furthermore, the analysis revealed a robust positive correlation between the decrease in phenytoin concentration level and several factors, including blood loss during surgery, the duration of the surgical procedure, intravenous fluids administered during surgery, and the occurrence of postoperative seizures. Conclusion This study underscores the potential utility of routinely measuring perioperative serum phenytoin levels in high-risk patients to prevent postcraniotomy seizures. Moreover, it suggests that patients with substantial intraoperative blood loss may benefit from an additional bolus dose of phenytoin toward the end of the surgical procedure.

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of CYP2C9, HLA-A and HLA-B with anti-epileptic drugs.

By developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy, the Dutch Pharmacogenetics Working Group (DPWG) aims to advance the implementation of pharmacogenetics (PGx). This guideline outlines the gene-drug interaction of CYP2C9 and HLA-B with phenytoin, HLA-A and HLA-B with carbamazepine and HLA-B with oxcarbazepine and lamotrigine. A systematic review was performed and pharmacotherapeutic recommendations were developed. For CYP2C9 intermediate and poor metabolisers, the DPWG recommends lowering the daily dose of phenytoin and adjust based on effect and serum concentration after 7-10 days. For HLA-B*15:02 carriers, the risk of severe cutaneous adverse events associated with phenytoin, carbamazepine, oxcarbazepine, and lamotrigine is strongly increased. For carbamazepine, this risk is also increased in HLA-B*15:11 and HLA-A*31:01 carriers. For HLA-B*15:02, HLA-B*15:11 and HLA-A*31:01 positive patients, the DPWG recommends choosing an alternative anti-epileptic drug. If not possible, it is recommended to advise the patient to report any rash while using carbamazepine, lamotrigine, oxcarbazepine or phenytoin immediately. Carbamazepine should not be used in an HLA-B*15:02 positive patient. DPWG considers CYP2C9 genotyping before the start of phenytoin "essential" for toxicity prevention. For patients with an ancestry in which the abovementioned HLA-alleles are prevalent, the DPWG considers HLA-B*15:02 genotyping before the start of carbamazepine, phenytoin, oxcarbazepine, and lamotrigine "beneficial", as well as genotyping for HLA-B*15:11 and HLA-A*31:01 before initiating carbamazepine.

Topical Phenytoin Improves Wound Healing With Analgesic and Antibacterial Properties and Minimal Side Effects: A Systematic Review

Background. Although phenytoin's potential benefits in wound healing, pain relief, and infection control across various wound types have been previously reported, its use in wound care remains limited. Objective. To conduct a comprehensive review to assess the efficacy of topical phenytoin compared with standard and alternative treatments for different wound types. Materials and Methods. The authors last searched Cochrane Library, PubMed, PubMed Central, and MEDLINE in June 2023. All English-language human RCTs and NRCTs from any time were included. The RoB 2 was used to assess quality of randomized trials, and the ROBINS-I was used to assess the quality of nonrandomized trials. Studies with a low risk of bias or some concerns in no more than 1 domain were included. Data collected and analyzed included wound type, interventions, sample size, outcome measures, and adverse effects. Results. The search yielded 101 studies, of which 17 RCTs and 8 NRCTs were eligible for inclusion. Of the included studies, 56% had a low risk of bias in all domains. The sample sizes varied between 20 and 130 (median, 60), with a total sample size of 1653 patients. Phenytoin improved wound healing in 17 of the 24 studies that evaluated it (71%), increased granulation tissue in 9 of the 10 studies that evaluated it (90%), provided analgesic effects in 7 of the 13 studies that evaluated it (54%), and inhibited bacterial contaminants in 6 of the 8 studies that evaluated it (75%). Adverse effects were rare (29%), minimal, and transient. Conclusion. Phenytoin enhances wound healing and offers analgesic and antibacterial properties with minimal adverse effects. Further research is needed on optimal dosage of phenytoin, as well as frequency, delivery vehicles, and effects on other postoperative wounds. Background. Although phenytoin’s potential benefits in wound healing, pain relief, and infection control across various wound types have been previously reported, its use in wound care remains limited. Objective. To conduct a comprehensive review to assess the efficacy of topical phenytoin compared with standard and alternative treatments for different wound types. Materials and Methods. The authors last searched Cochrane Library, PubMed, PubMed Central, and MEDLINE in June 2023. All English-language human RCTs and NRCTs from any time were included. The RoB 2 was used to assess quality of randomized trials, and the ROBINS-I was used to assess the quality of nonrandomized trials. Studies with a low risk of bias or some concerns in no more than 1 domain were included. Data collected and analyzed included wound type, interventions, sample size, outcome measures, and adverse effects. Results. The search yielded 101 studies, of which 17 RCTs and 8 NRCTs were eligible for inclusion. Of the included studies, 56% had a low risk of bias in all domains. The sample sizes varied between 20 and 130 (median, 60), with a total sample size of 1653 patients. Phenytoin improved wound healing in 17 of the 24 studies that evaluated it (71%), increased granulation tissue in 9 of the 10 studies that evaluated it (90%), provided analgesic effects in 7 of the 13 studies that evaluated it (54%), and inhibited bacterial contaminants in 6 of the 8 studies that evaluated it (75%). Adverse effects were rare (29%), minimal, and transient. Conclusion. Phenytoin enhances wound healing and offers analgesic and antibacterial properties with minimal adverse effects. Further research is needed on optimal dosage of phenytoin, as well as frequency, delivery vehicles, and effects on other postoperative wounds.

Improvement of solubility, dissolution, and bioavailability of phenytoin intercalated in Mg-Al layered double hydroxide.

Layered double hydroxides (LDHs) are highly effective drug delivery systems, owing to their capacity to intercalate or adsorb biomaterials, flexible structure, swelling property, high stability, good biocompatibility, and ease of synthesis. Phenytoin (PHT) is an antiseizure BCS (Biopharmaceutics Classification System) class II drug, presenting low aqueous solubility. Therefore, the current study aimed at increasing its solubility, dissolution, and bioavailability. PHT was intercalated to the MgAl-LDH formed in situ and successful intercalation to form MgAl-PHT-LDH was confirmed by FTIR, PXRD, DSC, and TGA. Examination of particle size and morphology (by photon correlation spectroscopy and electron microscopy, respectively) confirmed the formation and intercalation of nanostructured LDH. Intercalation enhanced the saturation solubility of PHT at 25°C in 0.1N HCl and phosphate buffer (pH 6.8) by 6.57 and 10.5 times respectively. The selected drug excipient powder blend for the formulation of MgAl-PHT-LDH tablets exhibited satisfactory properties in both pre-compression parameters (angle of repose, bulk density, tapped density, Carr's index, and Hausner ratio) and tablet characteristics (weight variation, thickness, hardness, friability, content uniformity, and disintegration time). MgAl-PHT-LDH tablets showed better dissolution of PHT compared to unprocessed PHT tablets at all time points. Oral bioavailability of MgAl-PHT-LDH tablets and unprocessed PHT tablets was tested in two groups of Sprague Dawley rats based on analysis of serum levels of both forms of PHT by UPLC-ESI-MS/MS serum. MgAl-PHT-LDH tablets demonstrated a relative bioavailability of 130.15% compared to unprocessed PHT tablets, confirming a significantly higher oral bioavailability of MgAl-PHT-LDH. In conclusion, MgAl-PHT-LDH could provide a strategy for enhancing solubility, dissolution, and thereby bioavailability of PHT, enabling the evaluation of theclinical efficacy of MgAl-PHT-LDH tablets for the treatment of seizures at lower PHT doses.

An analysis of the Michaelis-Menten pharmacokinetics of phenytoin in epileptic Indonesian adults

Background: Phenytoin metabolism has been shown to vary in different ethnic groups. Therefore, the authors studied phenytoin pharmacokinetics in Indonesian adult patients with epilepsy. Objective: The purpose of this study was to determine and analyse the pharmacokinetic parameters of Michaelis Menten Vmax (maximum velocity) and Km (the Michaelis constant) of phenytoin in adult epileptic patients. Method: Twelve adult epileptic patients were chosen on the basis that they had two reliable steady-state phenytoin serum levels at two different daily doses and they required an additional adjustment of phenytoin dosage monotherapy. Result: The Vmax and Km values for adult epileptic patients respectively, ranged from 3.78 to 9.65 mg/kg/day and from 0.71 to 5.58 mg/L and there was no correlation with age and weight (p &gt; 0.05). The Vmax and Km values have shown individual variability. Conclusion: The optimal adjustment of phenytoin dose individually in adult epileptic patients based on Vmax and Km parameters needs to be done to get the desired steady-state level according to the clinical response.

Hodgkin lymphoma patient presenting as superior vena cava syndrome in a patient suffering from myotonia congenita: A rare case scenario

A 14-year-old male who was a known case of myotonia congenital (MC) (SCN4A mutation related) on Tab phenytoin therapy presented with progressive shortness of breath, swelling of face, and intermittent fever for 2 months. On investigation, a middle mediastinal mass was diagnosed and histopathological examination along with immunohistochemistry revealed it to be Hodgkin lymphoma (HL). The patient was started on Inj. dexamethasone for superior vena cava syndrome followed by doxorubicin, vincristine, etoposide, and prednisolone chemotherapy and phenytoin dose adjustment. The patient responded well to treatment. This case summarizes the management in patients of HL presenting as superior vena cava syndrome in a background of MC on enzyme inducer therapy.

Association of epilepsy, anti-epileptic drugs (AEDs), and type 2 diabetes mellitus (T2DM): a population-based cohort retrospective study, impact of AEDs on T2DM-related molecular pathway, and via peroxisome proliferator-activated receptor γ transactivation.

A potential association between epilepsy and subsequent type 2 diabetes mellitus (T2DM) has emerged in recent studies. However, the association between epilepsy, anti-epileptic drugs (AEDs), and the risk of T2DM development remains controversial. We aimed to conduct a nationwide, population-based, retrospective, cohort study to evaluate this relationship. We extracted data from the Taiwan Longitudinal Generation Tracking Database of patients with new-onset epilepsy and compared it with that of a comparison cohort of patients without epilepsy. A Cox proportional hazards regression model was used to analyze the difference in the risk of developing T2DM between the two cohorts. Next-generation RNA sequencing was used to characterize T2DM-related molecularchanges induced by AEDs and the T2DM-associated pathways they alter. The potential of AEDs to induce peroxisome proliferator-activated receptor γ (PPARγ) transactivation was also evaluated. After adjusting for comorbidities and confounding factors, the case group (N = 14,089) had a higher risk for T2DM than the control group (N = 14,089) [adjusted hazards ratio (aHR), 1.27]. Patients with epilepsy not treated with AEDs exhibited a significantly higher risk of T2DM (aHR, 1.70) than non-epileptic controls. In those treated with AEDs, the risk of developing T2DM was significantly lower than in those not treated (all aHR ≤ 0.60). However, an increase in the defined daily dose of phenytoin (PHE), but not of valproate (VPA), increased the risk of T2DM development (aHR, 2.28). Functional enrichment analysis of differentially expressed genes showed that compared to PHE, VPA induced multiple beneficial genes associated with glucose homeostasis. Among AEDs, VPA induced the specific transactivation of PPARγ. Our study shows epilepsy increases the risk of T2DM development, however, some AEDs such as VPA might yield a protective effect against it. Thus, screening blood glucose levels in patients with epilepsy is required to explore the specific role and impact of AEDs in the development of T2DM. Future in depth research on the possibility to repurpose VPA for the treatment of T2DM, will offer valuable insight regarding the relationship between epilepsy and T2DM.

Global distribution of functionally important CYP2C9 alleles and their inferred metabolic consequences

BackgroundGenetic variability in the cytochrome P450 CYP2C9 constitutes an important predictor for efficacy and safety of various commonly prescribed drugs, including coumarin anticoagulants, phenytoin and multiple non-steroidal anti-inflammatory drugs (NSAIDs). A global map of CYP2C9 variability and its inferred functional consequences has been lacking.ResultsFrequencies of eight functionally relevant CYP2C9 alleles (*2, *3, *5, *6, *8, *11, *13 and *14) were analyzed. In total, 108 original articles were identified that included genotype data from a total of 81,662 unrelated individuals across 70 countries and 40 unique ethnic groups. The results revealed that CYP2C9*2 was most abundant in Europe and the Middle East, whereas CYP2C9*3 was the main reason for reduced CYP2C9 activity across South Asia. Our data show extensive variation within superpopulations with up to tenfold differences between geographically adjacent populations in Malaysia, Thailand and Vietnam. Translation of genetic CYP2C9 variability into functional consequences indicates that up to 40% of patients in Southern Europe and the Middle East might benefit from warfarin and phenytoin dose reductions, while 3% of patients in Southern Europe and Israel are recommended to reduce starting doses of NSAIDs.ConclusionsThis study provides a comprehensive map of the genetic and functional variability of CYP2C9 with high ethnogeographic resolution. The presented data can serve as a useful resource for CYP2C9 allele and phenotype frequencies and might guide the optimization of genotyping strategies, particularly for indigenous and founder populations with distinct genetic profiles.

Efficacy of 48 hours dose of phenytoin in prevention of early post-traumatic seizure

BackgroundAntiseizure medications, such as phenytoin sodium, have been shown in some reports to reduce the incidence of early post-traumatic seizure. These medications, however, are not without side effects which may...

Purple Glove Syndrome- A Catastrophic Complication of Phenytoin Injection

Purple Glove Syndrome (PGS) is a rare complication of intravenous phenytoin administration which is illustrated by delayed soft tissue injury of the skin conterminous to the point or distal to the site of intravenous phenytoin infusion. The clinical features of PGS include pain, oedema, and bluish discolouration over the extremity. The present case report describes about a 60-year-old male, who presented to the Emergency Department with the chief complaints of generalised tonic clonic seizures, lasting for 10 mins, for which he was managed with inj. phenytoin sodium. The computed tomography scan of brain revealed right-sided subdural haematoma. After 24 hours of hospital stay, the patient started complaining of severe pain in the arm and forearm. There was purple-bluish discolouration around the intravenous site, peripheral oedema and pain. The various risk factors linked to PGS, include old age and large and multiple doses of phenytoin.

Dose Adjustment of Concomitant Antiseizure Medications During Cenobamate Treatment: Expert Opinion Consensus Recommendations.

Our objective was to provide expert consensus recommendations to improve treatment tolerability through dose adjustments of concomitant antiseizure medications (ASMs) during addition of cenobamate to existing ASM therapy in adult patients with uncontrolled focal seizures. A panel of seven epileptologists experienced in the use of ASMs, including cenobamate, used a modified Delphi process to reach consensus. The panelists discussed tolerability issues with concomitant ASMs during cenobamate titration and practical strategies for dose adjustments that may prevent or mitigate adverse effects. The resulting recommendations consider concomitant ASM dose level and specify proactive (prior to report of an adverse effect) and reactive (in response to report of an adverse effect) dose adjustment suggestions based on concomitant ASM pharmacokinetic and pharmacodynamic interactions with cenobamate. Specific dose adjustment recommendations are provided. We recommend proactively lowering the dose of clobazam, phenytoin, and phenobarbital due to their known drug-drug interactions with cenobamate, and lacosamide due to a pharmacodynamic interaction with cenobamate, to prevent adverse effects during cenobamate titration. Reactive lowering of a concomitant ASM dose is sufficient for other ASMs at standard dosing owing to quick resolution of adverse effects. For carbamazepine and lamotrigine doses exceeding the upper end of standard dosing (e.g., carbamazepine, greater than 1200mg/day; lamotrigine, greater than 500mg/day), we encourage consideration of proactive dose reduction at cenobamate 200mg/day to prevent potential adverse effects. All dose reductions for adverse effects can be repeated every 2weeks as dictated by the adverse effects. At cenobamate 200mg/day, we recommend that patients be evaluated for marked improvement of seizures and further dose reductions be considered to reduce potentially unnecessary polypharmacy. The primary goal of the recommended dose reductions of concomitant ASMs is to prevent or resolve adverse effects, thereby allowing cenobamate to reach the optimal dose to achieve the maximal potential of improving seizure control.

Evaluation of phenytoin loading doses in overweight patients using actual versus adjusted body weight

Background and ObjectivesThe appropriate loading dose strategy for phenytoin/fosphenytoin in overweight patients is unknown. A small pharmacokinetic study indicated that overweight patients have a higher volume of distribution and potentially would benefit from using adjusted body weight (AdjBW) instead of actual body weight (ABW) to calculate the loading dose. The purpose of this study was to determine the optimal loading dose strategy of phenytoin in patients whose ABW is greater than 120% of their ideal body weight (IBW) using either ABW or AdjBW for calculation of the loading dose. MethodsThis was a single center, retrospective study which included patients who received a loading dose of phenytoin of at least 10 mg/kg based on ABW, had a phenytoin level drawn <6 h after the end of the dose, and weighed ≥120% of their IBW. Patients were excluded if they received intramuscular phenytoin or fosphenytoin or were prescribed phenytoin prior to the loading dose. Patients were divided into two groups, those who were dosed using their AdjBW versus those dosed using ABW. The primary outcome was achievement of therapeutic phenytoin level of 10–20 mcg/mL. Secondary outcomes included achievement of a subtherapeutic or supratherapeutic level. ResultsA total of 195 patients (128 in AdjBW group and 67 in ABW group) met criteria for inclusion. Patients in the AdjBW group weighed more (96.2 kg vs. 91.2 kg, p = 0.04) and received a lower dose in milligrams (1364 vs. 1760, p < 0.0001) and in mg/kg of ABW (14.2 vs. 19.3, p < 0.0001). The primary outcome was achieved in 74% of patients in the AdjBW group and 57% of patients in the ABW group (p = 0.02). Patients in the ABW group were more likely to have a supratherapeutic level (43% vs. 22%, p = 0.003), although adverse reactions did not differ between the groups. DiscussionPatients weighing >120% of their IBW (average body mass index 33.5 kg/m2) who received a 20 mg/kg loading dose based on AdjBW were more likely to achieve a therapeutic phenytoin concentration compared to those dosed based on ABW. Further research is needed to correlate this finding with clinical outcomes, such as resolution of status epilepticus.

Estimation of Free Phenytoin Concentration in Critically Ill Patients with Hypoalbuminemia: Direct-measurement vs Traditional Equations.

BackgroundIn critically ill patients with low albumin, dose individualization of phenytoin is a challenge. The currently used Sheiner–Tozer equation does not accurately predict the free phenytoin concentration in serum and can result in incorrect dose modifications. The best measure to advocate in these patients is the direct-measurement of free phenytoin concentration.Aims and objectivesPhenytoin exhibits complex pharmacokinetics, requiring careful therapeutic drug monitoring. This study aimed to compare the accuracy of the established Sheiner–Tozer calculation method against the direct-measurement of free phenytoin concentration in serum by high performance liquid chromatography in critically ill patients with low albumin.Materials and methodsBlood specimens for direct-measurement of both total and free phenytoin concentration were obtained from 57 patients with hypoalbuminemia monitored in the intensive care unit.ResultsThe median [inter-quartile range (IQR)] for Sheiner–Tozer equation calculated total phenytoin concentration and direct-measured total was 17.14 (10.63–24.53) and 9.82 (6.02–13.85) μg mL−1, respectively. Approximately 53 and 5% of patients were found to be subtherapeutic and supratherapeutic for direct-measured total phenytoin concentrations, respectively. In contrast, on applying the Sheiner–Tozer calculation, 23 and 40% had subtherapeutic and supratherapeutic concentrations, respectively, for total phenytoin concentration. The median (IQR) for direct-measured, routine and Sheiner–Tozer equation calculated free phenytoin concentration were 1.92 (1.06–2.76), 0.98 (0.60–1.39), and 1.71 (1.06–2.45) μg mL−1, respectively. Only 45.7% of patients were in agreement with respect to the therapeutic category when direct-measured free was compared against routine calculation free.ConclusionIn patients with low albumin, free phenytoin concentration based on the Sheiner–Tozer corrected equation accurately classified patients based on their therapeutic category of free phenytoin in 73.7% of patients. Hence, for individualization of phenytoin dosage in critically ill patients with low albumin, we recommend direct-measurement of free phenytoin concentration.How to cite this articleWilfred PM, Mathew S, Chacko B, Prabha R, Mathew BS. Estimation of Free Phenytoin Concentration in Critically Ill Patients with Hypoalbuminemia: Direct-measurement vs Traditional Equations. Indian J Crit Care Med 2022;26(6):682–687.

Phenytoin Metabolic Ratio, a Marker of CYP2C9 Activity, is Superior to the CYP2C9 Genotype as a Predictor of (S)-Warfarin Clearance.

CYP2C9 is a member of the cytochrome P450 (CYP) superfamily responsible for the metabolism of 16% of drugs that undergo oxidative metabolism. The activity of CYP2C9 exhibits marked inter-individual variability, which translates into prominent differences in the pharmacokinetics of CYP2C9 substrates, some of which are characterized by a narrow therapeutic window. Genetic polymorphisms in the gene encoding for CYP2C9 account for a fraction of the variability in CYP2C9 activity. The phenytoin metabolic ratio (PMR) is a marker of CYP2C9 activity in vivo, which correlates with CYP2C9 genetic polymorphisms. The purpose of the current study was to evaluate the ability of the PMR to predict the oral clearance of (S)-warfarin (SWOCL) and its formation clearance towards its CYP2C9-mediated metabolites (SWCLf) [i.e., 6- and 7-hydroxy-(S)-warfarin]. The study was conducted in 150 healthy non-smoker subjects (segment 1) and 60 patients treated with warfarin (segment 2). In the first segment, the participants received on two separate occasions a single 300-mg dose of phenytoin and at least 7 days later a single dose of warfarin (5 or 10 mg). The same PMR procedure was performed in the second segment, except that it was performed either before warfarin initiation or after the patients had reached stable anticoagulation. The PMR was derived from the ratio of 5-(4-hydroxyphenyl)-5-phenyl-hydantoin content in a 24-hour urine collection to plasma phenytoin concentration 12- (PMR24/12) or 24- (PMR24/24) post-dosing. In segment 1, SWOCL was calculated from the ratio of (S)-warfarin dose to the warfarin area under the plasma concentration-time curve extrapolated to infinity and the SWCLf from the ratio of urine content of 6- and 7-hydroxy-(S)-warfarin to (S)-warfarin area under the (S)-warfarin plasma concentration-time curve until the last measured timepoint. In segment 2, estimated SWOCL was derived from the ratio of (S)-warfarin dose to the mid-interval plasma concentration of (S)-warfarin. The PMR, SWOCL, and SWCLf varied significantly between carriers of different CYP2C9 genotypes in both healthy subjects (p < 0.001) and patients (p < 0.005). However, PMR and SWOCL values exhibited substantial intra-genotypic variability. PMR24/12 and PMR24/24 were significantly correlated with SWOCL both in healthy subjects (r = 0.62 and r = 0.67, respectively, p < 0.001) and in patients (r = 0.57 and r = 0.61, respectively, p < 0.001). In a multiple regression model that included all variables that correlated with SWOCL, PMR was the strongest predictor, explaining 44% and 38% of the variability in SWOCL among healthy subjects and patients, respectively, and accounting for 95.7% (44%/46%) and 90.5% (38%/42%) of the total explained variability in SWOCL among healthy subjects and patients, respectively. The PMR is the strongest predictor of SWOCL, and as such, it exhibits a significant advantage over the CYP2C9 genotype. The inclusion of PMR in future dosing algorithms of CYP2C9 substrates characterized by a narrow therapeutic window should be encouraged and further investigated.

Hurdles Faced by Healthcare Providers in Titrating Phenytoin Dosage in Long-Term Care

Medications are associated with development of adverse drug events (ADEs), some more than others, due to alteration in pharmacokinetics and dynamics with age. Phenytoin efficacy and toxicity relate to drug levels, interaction with cytochrome P450, hepatic function and albumin levels; phenytoin is largely protein bound. Our case illustrates the difficulties in dosing phenytoin in a long-term care resident.

Hurdles Faced By Healthcare Providers in Titrating Phenytoin Dosage in Long-Term Care

Medications are associated with development of adverse drug events (ADEs), some more than others, due to alteration in pharmacokinetics and dynamics with age. Phenytoin efficacy and toxicity relate to drug levels, interaction with cytochrome P450, hepatic function and albumin levels; phenytoin is largely protein bound. Our case illustrates the difficulties in dosing phenytoin in a long-term care resident.

Topical phenytoin administration accelerates the healing of acetic acid-induced colitis in rats: evaluation of transforming growth factor-beta, platelet-derived growth factor, and vascular endothelial growth factor.

Ulcerative colitis (UC), limited to the colon's innermost lining, has become a global health problem. Immunomodulatory and monoclonal antibodies are used to treat UC despite their side effects and limitations. Phenytoin is used to heal wounds owing to its effects on growth factors, collagen, and extracellular matrix synthesis. This study aimed to evaluate the effect of topical phenytoin administration in UC. Phenytoin was administered in two doses during the treatment. Eighty male Wistar rats (230-280g) were divided randomly into ten groups of sham, control, hydrocortisone, phenytoin 1%, and 3% groups in 6- or 12-day treatment protocols. The UC model was induced by the administration of acetic acid 4% into the colon. Animals were killed on the 7th and 13th postoperative days. The main outcome measures included body weight loss, microscopic score, and ulcer index measured using specific criteria. Growth factors were measured by western blotting. Results illustrated that body weight loss was reversed in the treatment groups. Ulcer index had decreased on 6- and 12-day treatment protocols. Microscopic scores in 6-day enema treatment significantly decreased compared to the control groups. Transforming growth factor-beta (TGFβ) significantly increased in a time-dependent manner and platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) significantly increased in a time- and dose-dependent manner in phenytoin 1% and 3% in the 6- and 12-day protocols. Phenytoin dose- and time-dependently reversed weight loss. In addition, histopathological parameters included microscopic scores, and the ulcer index was decreased through the induction of growth factors TGFβ, PDGF, and VEGF and consequently accelerated ulcer healing.

Phenytoin-associated movement disorder: A literature review.

Phenytoin (PHT) was first synthesized as a barbiturate derivative and was approved in 1953 by the Food and Drug Administration. This work aimed to review the pathophysiology, epidemiology, clinical presentation, and treatment of PHT-associated movement disorders (MDs). Studies were searched in relevant databases (ScienceDirect, Google Scholar, Excerpta Medica, Latin American and Caribbean Health Sciences Literature, Medline, and Scientific Electronic Library Online) and were selected by two reviewers irrespective of language between 1963 and 2021. Papers of PHT-induced ataxia alone or tremor were excluded. In total, 127 reports with 219 individuals who developed MDs associated with PHT were encountered. MDs found: 126 dyskinesias, 49 myoclonus, 19 dystonia, 14 parkinsonism, 6 tics, 3 stuttering, and 2 restless legs syndrome. The mean age was 35 years (standard deviation [SD]: 23.5) and the predominant sex was male (53.4%). The mean PHT dose when the MD took place was 370.4 mg (SD: 117.5). A serum PHT concentration was reported in 103 cases, ranging from 4 to 110 μg/mL (median: 27.7 μg/mL). No significant relationship was found between PHT dose and age or PHT level. The mean onset time of PHT-associated MD was 23.4 months (SD: 4.4). The mean recovery time after MD management was 3.7 weeks (SD: 1.1). Regarding management, the most common form was PHT withdrawal in 90.4%. 86.3% of the individuals recovered fully. PHT-induced MD was extensively reported in the literature. Only general terms were used in the majority of the reports. The mechanisms underlying the adverse events caused by PHT probably depend on the presence of predisposing factors.