Serum Phenytoin Concentrations Research Articles

Phenytoin and enteral feedings: does evidence support an interaction?

To systematically review the reported interaction between oral dosage forms of phenytoin and enteral feeding formulations with respect to the evidence supporting or refuting its existence, proposed mechanism(s) underlying the interaction, and recommended interventions. We conducted a MEDLINE search (1966-April 2000) for English-language articles on phenytoin-enteral feeding interactions; the search terms used were phenytoin, enteral feeding, and/or interaction, and/or in vitro. This search was supplemented by a bibliographic review of all relevant articles. Prospective, randomized, controlled studies; prospective, nonrandomized, controlled studies; prospective, nonrandomized, uncontrolled studies; retrospective studies; clinical experience reports; case reports; in vitro studies; and letters were evaluated for relevant information. Data elements abstracted from these articles were study design, type (patients or healthy volunteers) and number of subjects involved, method of administration of phenytoin and enteral feeding, formulation of phenytoin, type of feeding (and whether it was continuous or interrupted), major findings, and proposed mechanisms of the interaction. Although four prospective, randomized, controlled trials in healthy human volunteers refute the existence of the interaction, there are numerous reports and studies showing dramatic decreases of serum phenytoin concentrations in patients when it is coadministered with enteral feeding formulations. Therefore, evidence supports the existence of this interaction in patients and in vitro studies, but not in healthy volunteers. Unfortunately, the exact mechanisms underlying this interaction remain unknown. Many methods have been devised to prevent and treat the interaction once it has occurred; however, a single, generally accepted, and practical intervention strategy is still lacking. The exact role of enteral feeding in this interaction is unclear due to the lack of prospective, randomized, controlled trials performed in patients. However, decreased serum phenytoin concentrations associated with enteral feeding may increase the risk of seizures. Clinicians should be aware of this potential drug-nutrient interaction and design a patient-specific care plan that includes consideration of the enteral feeding formulation and method of administration, as well as the phenytoin dosage form, schedule of administration, and monitoring.

Unexpected suppression of free phenytoin concentration by salicylate in uremic sera due to the presence of inhibitors: Maldi mass spectrometric determination of molecular weight range of inhibitors

Salicylate displaces phenytoin from protein binding leading to an increase in free phenytoin concentration. We observed unexpected decreases in free phenytoin concentration in the presence of salicylate. Serum pools containing no phenytoin or salicylate were supplemented with the same concentrations of phenytoin. Then to the aliquots of the individual pool, no salicylate (control), 150, 300 and 500 μg ml of salicylate (therapeutic range: 15–300 μg ml ) were added. Specimens were incubated at 37 °C for 2 h and after re-equilibration at room temperature for 20 min, total and free phenytoin (in the protein free ultrafiltrates) concentrations were measured using fluorescence polarization immunoassay on the TDx/FLX analyzer. We observed an increase in free phenytoin concentration from 1.91 μg ml (in the absence of salicylate) to 2.39 μg ml in the presence of 500 μg ml salicylate (total phenytoin: 13.3 μg ml ) in the normal pool. In sharp contrast, the free phenytoin concentrations decreased from an initial concentration of 3.82 μg ml to 2.52 μg ml in the presence of 500 μg ml of salicylate (total phenytoin: 13.2 μg ml ) in the uremic pool. We also treated the uremic pool with activated charcoal. In the original uremic pool, the initial free phenytoin concentration was 3.05 μg ml and the free concentrations then decreased to 2.28 μg ml in the presence of 300 μg ml of salicylate. In contrast, in the charcoal treated pool, the initial free phenytoin concentration increased from 1.61 μg ml to 3.23 μg ml in the presence of 300 μg ml of salicylate. More interestingly when uremic toxins were extracted back from charcoal with methanol and the dry residue was added to an aliquot of normal serum, the normal serum behaved like a uremic serum and free phenytoin concentration was significantly decreased in the presence of salicylate. When an aliquot of methanol extract was studied by Matrix-Assisted Laser Desorption lonization Mass Spectrometry (scan up to 10,000), we observed no peak at molecular weight over 551, indicating that these inhibitors are small molecules. We also identified hippuric acid as one of the inhibitors.

Is Precipitation with Sulphosalicylic Acid Valid for Obtaining Free Valproic Acid and Phenytoin?

The aim of this study was to compare ultrafiltration with protein precipitation with sulphosalicylic acid in the separation of free and protein-bound serum phenytoin and valproic acid. Blood samples from 49 epileptic patients chronically treated with phenytoin (27) and valproic acid (22) were assayed. Free phenytoin or valproic acid were determined by fluorescent polarization immunoanalysis. The results showed that the free serum concentrations obtained by protein precipitation (24.9 ± 8.3 and 2.55 ± 1.61 mg L−1 for valproic acid and diphenylhydantoin, respectively) were almost three-fold those from ultrafiltration (7.5 ± 6.2 and 0.86 ± 0.6 mg L−1, respectively). Protein separation using sulphosalicylic acid is not a valid technique for obtaining the free serum concentration of phenytoin or valproic acid.

A 13-year-old with an acute change in mental status

A 13-year-old boy with Lennox-Gastaut syndrome characterized by absence, myoclonic, complex-partial, and secondarily generalized tonic-clonic seizures, presents with progressive obtundation and loss of motor and verbal skills over a 2-day period. Initial evaluation revealed therapeutic phenytoin serum concentrations. This article discusses the differential diagnosis and management approach used in this setting, as well as the appropriate interpretation of antiepileptic drug serum concentrations.

Frequency of cytochrome P450 CYP2C9 variants in a Turkish population and functional relevance for phenytoin.

The genetically polymorphic cytochrome P450 enzyme CYP2C9 metabolizes many important drugs. We studied the frequency of the amino acid variants cysteine144 (CYP2C9*2 ) and leucine359 (CYP2C9*3 ) in a Turkish population and the correlation between genotype and phenotype using phenytoin as probe drug. CYP2C9 alleles *2 and *3 were measured in 499 unrelated Turkish subjects by PCR and restriction fragment length pattern analysis. Phenotyping was performed in a subgroup of 101 volunteers with a single oral dose of 300 mg phenytoin and concentration analysis in serum drawn 12 h after dosage. CYP2C9 allele frequencies in 499 unrelated Turkish subjects were 0.794 for CYP2C9*1, 0.106 for CYP2C9*2 and 0. 100 for CYP2C9*3. Mean phenytoin serum concentrations at 12 h after dosage were 4.16 mg l-1 (95% CI 3.86-4.46) in carriers of the genotype CYP2C9*1/1, 5.52 mg l-1 (4.66-6.39) in CYP2C9*1/2, and 5.65 mg l-1 (4.86-6.43) in CYP2C9*1/3. These differences were significant and accounted for 31% of total variability in phenytoin trough levels. Mean 12 h concentration ratios of 5-(para-hydroxyphenyl)-5-phenylhydantoin/phenytoin (p-HPPH/P) were 0. 43 (0.39-0.47) for CYP2C9*1/1 compared with 0.26 (0.21-0.31) for CYP2C9*1/2, 0.14 (0.13-0.14) for CYP2C9*2/2, 0.21 (0.18-0.24) for CYP2C9*1/3, and 0.02 for CYP2C9*3/3; all mutant genotypes were significantly different compared with CYP2C9*1/1. Frequency of the two CYP2C9 variants in Turkish subjects was in a similar range as in other Caucasian populations. A significant proportion of the interindividual variability in phenytoin trough levels is explained by the genotypes. The 12 h serum concentrations after a single phenytoin dose may be used for routine phenotyping of CYP2C9 mediated metabolic clearance and the p-HPPH/P ratios may be even more sensitive indicators of CYP2C9 activity.

The Effect of Time of Administration of Phenytoin on its Serum Levels and Pharmacodynamic Parameters in Patients of Generalised Tonic Clonic Seizures

The role of the time of administration of phenytoin on its serum levels and pharmacodynamic parameters was studied in two comparable groups of patients of grand mal_epilepsy stabilized on serum phenytoin therapy. In these patients, phenytoin was advised to be taken as a single daily dose either at 08.00 (Group M) or 20.00 (Group E) every day. A serum phenytoin level profile over 24 hours was obtained and all patients were clinically followed up for six months. Maximum serum concentration (C-max) of phenytoin was achieved significantly faster (p < 0.001) in patients of Group E. The total number of serum samples having toxic concentrations and also the incidence and severity of toxic effects of phenytoin was less in Group E. The study suggests that bedtime administration of phenytoin in patients of grand mal–epilepsy may lead to faster absorption of the drug and less side effects as compared with drug administration in the morning.

Isoniazid drug and food interactions.

Isoniazid inhibits the metabolism of several drugs, resulting in clinically significant interactions in some patients. Clinical trials and case reports have documented that isoniazid can cause increased phenytoin and carbamazepine serum concentrations and toxicity. In relatively high doses, isoniazid can also cause increased effect of theophylline and warfarin. Isoniazid inhibits metabolism of selected benzodiazepines and vitamin D. Inhibition of monoamine oxidase and histaminase by isoniazid can cause significant drug-food interactions. Food greatly decreases isoniazid bioavailability. Although probably best recognized as an inhibitor of drug metabolism, isoniazid has a biphasic effect of inhibition-induction on one cytochrome P450 isozyme, CYP2E1, which partially explains the interaction with acetaminophen and increased risk of hepatotoxicity. Continued investigations will likely result in discovery of new isoniazid interactions.

Phenytoin dosage adjustment in Saudi epileptics: utilization of steady-state pharmacokinetic parameters.

We determined the Michaelis-Menten parameters (Vmax and Km) in 271 Saudi epileptic patients having generalized tonic-clonic seizures and who were treated with phenytoin (PHT) using high pressure liquid chromatography (HPLC). The patients comprised 150 (55.4%) males and 121 (44.6%) females, with a mean age of 31.7 years (SD = 18.5). The mean Vmax for subjects less than 16 years of age was 10.35 mg/kg/day (SD = 0.73, range = 3.77-17.01), while for those above 16 years, the mean value was 7.99 mg/kg/day (SD = 0.15, range = 3.68-15.95). The difference was statistically significant (P < 0.001). Vmax was positively correlated with weight (r = 0.953), but negative with age (r = -0.903). Km values ranged from 1.01-20.87 mg/litre. The adult Km mean of 6.52 mg/l (SD = 0.24) was significantly higher than the mean of 4.79 mg/l (SD = 0.40) for pediatric patients (P < 0.01), but Km was correlated neither with age nor with weight. Our results showed no difference between the predicted and observed serum PHT concentrations in both the pediatric and adult patients when the respective age group Km and Vmax values were used to adjust PHT doses. The pediatric cases, however, required 30% more PHT per kilogram of body weight than the adults for the achievement of similar serum concentrations.

ＣＹＰ２Ｃサブファミリーの遺伝子診断情報に基づくＰｈｅｎｙｔｏｉｎ個別投与設計法の評価

We estimated the population pharmacokinetic parameters of phenytoin in Japanese patients with epilepsy, and examined the effect of cytochrome P450 (CYP) 2C9/19 polymorphisms on the pharmacokinetics of phenytoin. In this study, we evaluated the phenytoin dosage regimen based on the simple polymerase chain reaction-based genetic test of CYP2C isozymes. The population pharmacokinetic parameters without the infor-mation of CYP2C genotypes failed to predict the serum phenytoin concentration in patients with the mutation in CYP2C9 (Ile359→Leu).In contrast, the genotyping of CYP 2C9/19 in individual patients was useful in determining which patients are at risk for drug intoxication. In addition, the precision of the predicted serum phenytoin concentra-tions was improved by the Bayesian analysis based on the population pharmacokinetic parameters involving the polymorphism of CYP2C subfamily. The genetic test for the CYP2C isozymes will be useful to determine the dosage regimen of phenytoin.

The effects of genetic polymorphisms of CYP2C9 and CYP2C19 on phenytoin metabolism in Japanese adult patients with epilepsy: studies in stereoselective hydroxylation and population pharmacokinetics.

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. 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. The mean maximal elimination rate (Vmax) was 42% lower in the heterozygote for Leu359 allele in CYP2C9, and the mean Michaelis-Menten constants (Km) 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 (S)-p-HPPH/PHT ratios were lower in patients with mutations in CYP2C9 or CYP2C19 gene than those in patients without mutations. 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.

Analytical performance of a new chemiluminescent phenytoin (ACS:180) assay.

The authors, as a beta testing site, evaluated the ACS:180-phenytoin chemiluminescent assay (Ciba-Corning Diagnostics Corp., Medfield, MA, U.S.A.) by comparing its performance with a widely used fluorescence assay for phenytoin (Abbott Laboratories, Abbott Park, IL, U.S.A.). The ACS:180-phenytoin assays were run on a ACS-180 analyzer and fluorescence polarization assays on a TDx analyzer. The within-run precision for ACS-phenytoin assay was determined using controls obtained from Ciba-Corning. The CVs were 2.9% for low control (mean = 5.5, SD = 0.16 microgram/ml, n = 10), 2.8% for the medium control (mean = 13.4, SD = 0.37 microgram/ml, n = 10), and 2.7% for the high control (mean = 24.6, SD = 0.66 microgram/ml, n = 10). The corresponding between run precisions were 4.1% for the low control (mean = 5.4, SD = 0.22 mg/ml, n = 10), 3.1% for the medium control (mean = 13.8, SD = 0.43 mg/ml, n = 10), and 2.9% (mean = 24.5, SD = 0.70 mg/ml, n = 10) for the high control. The assay was linear from 0.5 to 40 micrograms/ml of serum phenytoin concentrations with a detection limit of 0.24 microgram/ml. The recoveries were 93-97% for concentrations of phenytoin of 5-30 micrograms/ml. They also compared 111 serum specimens collected from patients receiving phenytoin. The concentrations of phenytoin ranged from none detected to 32.4 micrograms/ml. Using fluorescence polarization assay as x-axis (reference method) and ACS:180-phenytoin assay as y-axis, they obtained the following regression line: y = 1.0x - 0.26, r = 0.993. They conclude that the ACS-phenytoin assay has a good precision and that the results correlate well with the fluorescence polarization assay.

Single oral loading dose of phenytoin: a pharmacokinetics study

In order to determine the optimal single oral loading dose of phenytoin in patients with seizures, a two part study of phenytoin pharmacokinetics was conducted. In the first part, 15 mg/kg of phenytoin was given orally as a single dose to 19 normal medical volunteers with informed consent. Serum concentrations of phenytoin reached the therapeutic level (10 μg/ml) with an average of 2.62 ± 1.25 h. The peak concentrations at 7.26 ± 4.77 h was 11.95 ± 2.8 μg/ml. The oral loading doses, calculated from a model incorporating a first order of absorption and Michaelis-Menten elimination kinetics to yield the target phenytoin serum concentration of 15 μg/ml were 18.7 mg/kg in males and 24.8 mg/kg in females. The larger dose for females is probably required due to the higher total apparent volume of distribution in females than in males. In the second part, seven male and seven female patients with seizures with informed consent received these calculated dosage regimens. For these patients, a single oral loading dose of phenytoin rapidly produced therapeutic concentration (10 μg/ml) within an average of 2.04 ± 0.44 h in males and 2.35 ± 1.6 h in females with minimal side-effects. For males, the peak concentration at 9.71 ± 5.94 h was 23.89 ± 5.46 μg/ml and that for females was 21.46 ± 5.08 μg/ml at 7.71 ± 3.73 h, respectively. Oral loading dose of phenytoin is safe, effective and can be considered in patients who need prompt control of seizures within a few hours, particularly in those areas where medical facilities are limited. It may also replace the intravenous route of phenytoin when the intravenous route is contraindicated.

フェニトインの新規母集団パラメータに基づくベイジアン解析法の評価

We previously examined the methods for evaluating the population pharmacokinetics for Michaelis-Menten elimination, and estimated the population pharmacokinetic parameters of phenytoin in Japanese patients with epilepsy (Biol. Pharm. Bull., 19, 444, 1996). In the present study, we evaluated the predictive performance of the bayesian analysis based on this prior information. To estimate the individual pharmacokinetic parameters of phenytoin in 50 patients, 3 serum phenytoin concentration data at a stady-state after repetitive dosing were collected retrospectively for each subject. The bayesian analysis using from 1 to 2 feedback concentrations gave the accurate predictions for another dosage regimens. The bayesian regression-analysis method described here in thus appears to be useful for predicting the steady-state serum phenytoin concentration from the limited number of data obtained for therapeutic drug monitoring purposes.

PHENYTOIN‐INDUCED HYPERGLYCAEMIA MAY CONFOUND RAT CEREBROPROTECTION MODELS

1. The anticonvulsant phenytoin (PHT) has been used with variable success in animal models of cerebral ischaemia. Although PHT has been reported to alter glucose regulation in man, this potential effect has been largely ignored in animals. Because hyperglycaemia strongly influences the outcome of cerebral ischaemia, we sought to systematically delineate the effects of PHT on serum glucose in several rat strains. 2. We studied the PHT dose-response curve for serum PHT and glucose concentrations and several physiological variables. Phenytoin induces a significant, concentration-dependent hyperglycaemia, even in the ranges commonly used for humans and in animal models. 3. Hypothermia of several degrees was observed during PHT administration, but no hypotension or bradycardia was found. 4. Both hyperglycaemia and hypothermia must be considered when PHT is studied as a neuroprotective agent in animal models.

Pharmacokinetic interactions of the new antiepileptic drugs.

Therapy with traditional antiepileptic drugs is associated with a wide range of pharmacokinetic drug-drug interactions. In particular, enzyme induction, enzyme inhibition and displacement from protein binding may result in important changes in serum concentrations of antiepileptics. Relevant interactions have also been described for some new antiepileptics. Felbamate increases serum concentrations of phenytoin, phenobarbital and valproic acid (sodium valproate). On the other hand, it reduces concentrations of carbamazepine and increases concentrations of its metabolite carbamazepine-10,11-epoxide. Concentrations of felbamate itself are reduced by phenytoin and carbamazepine. Concentrations of lamotrigine are considerably increased by valproic acid and decreased by phenytoin, carbamazepine and phenobarbital (phenobarbitone). Vigabatrin reduces serum concentrations of phenytoin by approximately 20%. On the other hand, some new antiepileptics have the important advantage of not interfering with the metabolism of other antiepileptics; this is the case for gabapentin, lamotrigine and oxcarbazepine. Furthermore, the pharmacokinetics of gabapentin, oxcarbazepine and vigabatrin are independent of concomitant drugs. These aspects are especially important as, until now, new antiepileptics have been most often utilised as add-on therapy.

P.1.053 - Combined pharmakotherapy (Tramadon and mianserin) in chronic pain syndrome

The study was performed on 48 subjects divided into four groups: control (1), hypercholesterolemia (2), hypertriglyceridemia (3) and mixed hyperlipidemia (4), The concentration and pharmacokinetic parameters for total phenytoin were determined after a single oral dose of 300 mg. Hypercholesterolemia (HCh) and mixed hyperlipidemia (MHL) significantly influenced the pharmacokinetics of total phenytoin, while hypertriglyceridemia (HTG) was without effect. The mean serum concentration of phenytoin was significantly higher in the HCh and MHL groups as compared with the control from 12 to 72 h. A significant increase in AUC, and tmax was observed in the HCh group. No significant changes were found in the HTG group. In the MHL group, AUC increased and ct/F/bw decreased. It was shown that hypercholesterolemia and mixed hyperlipidemia change the pharmacokinetics of phenytoin.

Efficacy and tolerability study of ucb L059 in patients with refractory epilepsy

We compared the experimental drug ucb L059 with placebo as an add-on therapy in a single-blind, ascending-dose pilot study in 17 patients with refractory epilepsy. The dose of ucb L059 was increased every 4 weeks by 500 mg in a stepwise fashion from 500 to 2,000 mg/day, and patients were assessed at weekly intervals for efficacy and safety evaluation. Fourteen patients successfully completed 20 weeks of treatment with placebo and increasing doses of ucb L059. Three patients withdrew because of adverse events (AE) or lack of efficacy. Treatment with ucb L059 was associated with a significant reduction in partial seizures as compared with baseline or placebo. Six patients experienced >50% reduction in seizure frequency, and 3 others experienced a 25–50% reduction. ucb L059 was well tolerated, only mild or moderate AE were reported, including drowsiness, memory impairment, depression, and mood changes. No clinically significant changes in laboratory or safety evaluation was detected during treatment with ucb L059. A variable change in phenytoin (PHT) and ucb L059 was noted, with PHT serum concentrations increasing significantly in some patients. The results suggest that oral ucb L059 may be useful in the treatment of refractory partial epilepsy.

Phenytoin Toxicity Associated With Ticlopidine Administration

A case of phenytoin sodium toxicity that appeared to be related to the administration of ticlopidine hydrochloride was recently observed at the Prescott Veterans Affairs Medical Center in Arizona. Report of a Case. A 71-year-old man had been taking ticlopidine for treatment of transient ischemic attacks. Concurrent medications included phenytoin sodium (350 mg/d), phenobarbital (90 mg/d), and cholestyramine resin (4 g at bedtime). The dosage of the phenytoin therapy had not been changed over the last 6 years (serum phenytoin concentrations, 60 to 80 μmol/L [15 to 20 mg/L]). A serum phenytoin concentration of 60 μmol/L (15 mg/L) was noted 2 weeks before ticlopidine therapy was initiated. The dosage of the phenobarbital therapy had not been changed for more than 2 years. After 1 month of ticlopidine hydrochloride therapy (250 mg twice daily), the patient began complaining of difficulty in walking and bilateral leg weakness. Serum concentrations of phenytoin and

Phenytoin protein binding and dosage requirements during acute and convalescent phases following brain injury.

To longitudinally evaluate unbound and total serum phenytoin concentrations during intravenous phenytoin maintenance dosage and to determine the relationship among phenytoin protein binding, serum albumin, and unbound fatty acid concentrations in patients with head injuries during intensive care unit (ICU) and convalescent care. Serum albumin and phenytoin unbound fraction were determined twice weekly during ICU and convalescent care in 10 patients receiving phenytoin following acute brain injury. Phenytoin protein binding was also determined in 10 healthy control subjects. Longitudinal serum phenytoin concentrations associated with dosage adjustments targeted to achieve unbound phenytoin serum concentrations between 1.0 and 2.0 mg/L were documented during ICU and convalescent care. Longitudinal phenytoin binding was correlated with serum albumin and unbound fatty acid concentrations in neurotrauma patients. ICU patients received intravenous therapy for a mean of 15.0 days. The mean +/- SD initial phenytoin intravenous dosage regimen of 6.0 +/- 0.7 mg/kg/d resulted in mean +/- SD total and unbound phenytoin concentrations of 3.2 +/- 2.3 and 0.3 +/- 0.2 mg/L. Two patients had seizures associated with low phenytoin concentrations. Four patients continued to receive oral phenytoin therapy during convalescent care; phenytoin dosage requirements decreased over time in these patients. During acute and convalescent care, the phenytoin unbound fraction ranged from 6.0% to 18.3% and correlated with albumin (r2 = 0.61, p < 0.0001) but did not correlate with unbound fatty acid concentrations. The mean phenytoin unbound fraction was 10.1% and 8.9% for the ICU and convalescent patients with brain injuries, respectively, and was 7.0% for the healthy volunteers. Phenytoin protein binding was significantly correlated with albumin and was more variable in ICU and convalescent patients with brain injuries than in healthy volunteers. The high dosage requirements and subtherapeutic unbound phenytoin concentrations observed during acute care are best explained by increased metabolism. Phenytoin dosage requirements decreased during convalescence.

Predicting Unbound Phenytoin Concentrations in the Critically Ill Neurosurgical Patient

To assess the correlation of measured unbound phenytoin concentration (dphF) to estimated unbound concentration (dphEF) using the Sheiner-Tozer equation in critically ill patients in the neurosurgical intensive care unit. The dphF and total phenytoin (dphT) trough serum concentrations were measured during the first week of therapy in 17 consecutive patients with albumin concentrations less than 3.5 g/dL. Serum albumin concentrations were measured within 24 hours of serum phenytoin concentration measurement. A university-affiliated urban teaching hospital. The study population consisted of 17 neurosurgical patients who were at least 18 years old. The predictability of the Sheiner-Tozer equation was tested by measuring dphF, dphT, and serum albumin concentrations. Measured phenytoin concentrations were compared with phenytoin concentrations calculated from the Sheiner-Tozer equation. To estimate correlation between variables linear regression was calculated. Mean absolute value of error and mean error were estimated to assess precision and bias between measures, respectively. The mean +/- SD dphT was 13.05 +/- 5.15 mu g/mL. The measured dphF was 1.89 +/- 0.80 compared with 2.00 +/- 0.8 mu g/mL for the dphEF (NS). Regression analysis for dphEF versus dphF revealed a significant correlation (r2 = 0.94, p = 0.001). The mean absolute value of error for the Sheiner-Tozer equation to predict dphEF was 0.167, which was 9% of the mean value of dphEF (1.89). These results indicate that, in this population, the Sheiner-Tozer estimate of dphEF provides an unbiased, precise clinical estimate of dphF in patients for whom measured dphF is unavailable or impractical.