Total Phenytoin Concentrations Research Articles

Total phenytoin concentrations do not accurately predict free phenytoin concentrations in critically ill children*

To determine the relationship between estimated free, measured free, and measured total phenytoin levels in critically ill pediatric patients, assess the utility of the Sheiner-Tozer equation in predicting free phenytoin levels, and identify comedications that may influence phenytoin binding or confound attempts to maintain therapeutic concentrations. Retrospective chart review. Twenty-four-bed medical-surgical pediatric intensive care unit. Sixty critically ill pediatric patients receiving phenytoin for treatment of seizures in a large multidisciplinary intensive care unit. The linear correlation between free and total phenytoin concentrations was moderate (r = .795), but the mean difference between actual free concentrations and those estimated from total concentrations using the Sheiner-Tozer equation was -0.31 +/- 0.5 microg/mL (95% confidence interval, -1.3 to 0.7). This difference was of concern, as 10% of patients had toxic free levels (>2 microg/mL) when simultaneously measured total levels were therapeutic (<20 microg/mL). The mean free/total phenytoin ratio was 0.13 +/- 0.07 (range, 0.06-0.42) and varied considerably among patients. Free fractions were particularly elevated in children whose serum albumin concentrations were <2.5 g/dL (0.22, p < .001). However, the relationship between free phenytoin and serum albumin concentration appeared to be nonlinear. Coadministration of valproic acid and cefazolin also increased free fraction (p < .001). Measured total phenytoin concentrations are unreliable for directing therapy in critically ill children. In part, this is because phenytoin binding shows greater variability in this population than has been reported in adults. This phenomenon is exacerbated by coadministration of other highly protein-bound drugs. Instead, free phenytoin concentrations should be routinely measured in critically ill children to prevent possible intoxications and ensure therapeutic dosing. Corrections using the Sheiner-Tozer equation were unreliable.

Total phenytoin concentrations do not accurately predict free phenytoin concentrations in critically ill children

Total phenytoin concentrations do not accurately predict free phenytoin concentrations in critically ill children

Total phenytoin concentrations do not accurately predict free phenytoin concentrations in critically ill children

Total phenytoin concentrations do not accurately predict free phenytoin concentrations in critically ill children

Interactions of Serum Albumin, Valproic Acid and Carbamazepine with the Pharmacokinetics of Phenytoin in Cancer Patients

Phenytoin dosing is critical in cancer patients as to decreased absorption secondary to chemotherapy-induced gastrointestinal toxicity, increased phenytoin metabolism in the liver secondary to chemotherapy, extreme patient profile that falls outside the predicted pharmacokinetic population, frequent hypoalbuminaemia and polydrug treatment. A retrospective study to assess the variability of free phenytoin and the free fraction of phenytoin, as well as the influence of comedication on these parameters was performed in cancer patients by using a population approach. Two hundred fifty-eight data pairs of total phenytoin and free phenytoin were analysed from 155 cancer patients on stable phenytoin using non-linear mixed-effect modeling (NONMEM). Total and free phenytoin were determined using a fluorescence polarization immunoassay. An extensive model building procedure was subsequently used for covariate testing on the free fraction of phenytoin. Mean total phenytoin concentration was 11.7 mg/l, free phenytoin 1.25 mg/l and phenytoin free fraction 0.107. Free phenytoin was <1 mg/l on 132 occasions (51.2%) and >2 mg/l on 37 occasions (14.3%). Total and free phenytoin were significantly correlated (r(S)=0.827, P<0.01). The free fraction of phenytoin was independent of time after drug intake. Serum albumin concentrations and comedication with valproic acid or carbamazepine were identified by NONMEM as significant determinants of phenytoin free fraction. Co-medication with valproic acid and carbamazepine led to a 52.5% and 38.5% increase of the free fraction of phenytoin, respectively, and a 10 g/l decrease of serum albumin to a 15.1% increase of the free fraction of phenytoin. Phenytoin pharmacokinetics could reliably be estimated from oral doses and steady-state concentrations of protein-bound and free phenytoin. The variability in the free fraction of phenytoin could partly be explained by the influence of albumin concentrations and antiepileptic comedication. Significant alterations of the free fraction of phenytoin and free phenytoin by co-administration of valproic acid or carbamazepine suggest therapeutic drug monitoring of free phenytoin to be of potential benefit in cancer patients.

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.

Lower phenytoin serum levels in persons switched from brand to generic phenytoin

After generic phenytoin (PHT) was marketed, the authors identified eight adult patients (ages 34 to 49) whose seizures increased enough to require intervention after switching to generic PHT. The mean total PHT concentration on brand (before generic) was 17.7 ± 5.3 mg/L, decreased to 12.5 ± 2.7 mg/L with generic, and increased to 17.8 ± 3.9 mg/L after brand was re-introduced. Brand and generic PHT do not yield equivalent concentrations in some patients and substitution should not be permitted without physician notification.

Lower phenytoin serum levels in persons switched from brand to generic phenytoin

After generic phenytoin (PHT) was marketed, the authors identified eight adult patients (ages 34 to 49) whose seizures increased enough to require intervention after switching to generic PHT. The mean total PHT concentration on brand (before generic) was 17.7 +/- 5.3 mg/L, decreased to 12.5 +/- 2.7 mg/L with generic, and increased to 17.8 +/- 3.9 mg/L after brand was re-introduced. Brand and generic PHT do not yield equivalent concentrations in some patients and substitution should not be permitted without physician notification.

Phenytoin Sodium as a Treatment for Ventricular Dysrhythmia in Horses

Five adult horses with ventricular extra systoles (VES) and 2 with ventricular tachycardia (VT) refractory to treatment with rest, anti‐inflammatory drugs, lidocaine, or procainamide were treated with phenytoin sodium PO q12h. The starting dosage of phenytoin was 20 or 22 mg/kg body weight (BW) q12h, and the maintenance dosage varied from 8 to 17 mg/kg BW q12h. The mean ± standard deviation therapeutic blood concentration of total phenytoin was 8.8 ± 2.1 mg/L, and the mean concentration of free phenytoin of 2.5 ± 0.5 mg/L was relatively constant at a range of 24 to 29% of the total phenytoin concentration. In all horses, both VES and VT were abolished after treatment with phenytoin. On the basis of the results of this clinical study, the authors propose an initial dose of 20 mg/kg BW q12h for the first 3 or 4 dosages, followed by a maintenance dose of 10 to 15 mg/kg BW q12h. Phenytoin plasma concentrations should be monitored during therapy. High plasma concentrations were associated with adverse effects such as recumbency and excitement. In this study, which included a limited number of diverse patients, phenytoin sodium appeared to be an inexpensive and effective treatment for persistent VES or VT in cases where conventional treatment had failed.

Influence of aging on serum phenytoin concentrations: a pharmacokinetic analysis based on therapeutic drug monitoring data

The influence of aging on the pharmacokinetics of phenytoin at steady-state was evaluated retrospectically by comparing apparent oral clearance values (CL/ F) in 75 patients aged 65–90 years (mean, 71.7 ± 5.3 years) receiving phenytoin alone ( n = 58) or in combination with phenobarbital ( n = 17) and in an equal number of control patients aged 20–50 years (mean, 36.7 ± 8.5 years) matched for gender, body weight, and comedication. All data were derived from the database of the therapeutic drug monitoring service (TDMS) of an academic neurological hospital. On average, elderly patients were found to exhibit slightly higher CL/ F values compared with controls (14.6 ± 4.7 ml h −1 kg −1 versus 13.1 ± 4.2 ml h −1 kg −1, P < 0.05), the difference being probably related to the dose-dependent nature of phenytoin metabolism and the fact that elderly patients received lower dosages (4.4 ± 1.1 mg kg −1 day −1 versus 5.3 ± 1.1 mg kg −1 day −1, P < 0.001) and had lower serum phenytoin concentrations (14.1 ± 5.7 μg ml −1 versus 18.6 ± 6.8 μg ml −1, P < 0.0001). Gender and phenobarbital comedication were not found to exert any statistically significant influence on phenytoin CL/ F. By contrast, in the elderly group, CL/ F values were negatively correlated with age. On average, CL/ F values decreased by about one-third between 65 and 85 years of age, but interindividual variability was considerable and age explained only 7.8% of the variation in CL/ F in the elderly group. Overall, these findings indicate that aging is associated with a progressive decline in phenytoin clearance, presumably as a result of decreased drug metabolizing capacity. Because assessment was based on total serum phenytoin concentrations and the unbound fraction of phenytoin is known to decrease in old age, the influence of aging as quantified in this study may underestimate the magnitude of changes in the clearance of unbound, pharmacologically active drug. Based on these data, it is prudent to utilize initially smaller phenytoin dosages in old patients, and to make subsequent dose adjustments based on clinical response and serum drug level measurements. Interpretation of the latter, however, should take into account the possibility of an increase in the fraction of unbound drug.

Phenytoin use in elderly nursing home residents

Background: Phenytoin (PHT) dosing regimens are often determined based on experience in those aged < 65 years rather than in those aged ≥65 years. Objective: The goal of this study was to determine the impact of sex, age, receipt of concomitant inhibitors or inducers of PHT metabolism, and albumin levels on doses and total serum concentrations of PHT in elderly nursing home residents. Methods: Consulting pharmacists to nursing homes located throughout the United States collected data from June 1998 to December 2000. The mean daily dose per person and mean total serum PHT concentration were tested for statistical differences by sex, age group (6–74, 75–84, and ≥85 years), coadministration of PHT inhibitors or inducers, and albumin levels. Results: Data were collected from 387 residents (259 women, 128 men) of 112 nursing homes in 19 states who received PHT and for whom PHT concentrations were available. The mean (SD) age of the study population was 79.4 (7.8) years; women constituted 67.0% of the study population. The mean (SD) total daily dose and total PHT concentration were 4.9 (1.8) mg/kg and 11.7 (6.4) mg/L, respectively. In general, women received higher mean (SD) daily doses of PHT compared with men (5.1 [1.8] vs 4.6 [1.6] mg/kg, respectively; P = 0.017) to achieve similar total serum concentrations (11.6 [6.4] and 12.0 [6.6] mg/L). PHT doses and serum concentrations were similar between age groups. There were no differences in daily doses (mg/kg or mg/d) or total serum concentrations of PHT based on concomitant use of inhibitors or inducers of PHT metabolism or on albumin levels, Conclusions: In this study in elderly nursing home residents, women received higher doses of PHT than men to achieve similar total serum PHT concentrations. There were no differences in doses or total serum PHT concentrations by age group, use of concomitant inducers or inhibitors of PHT metabolism, or albumin levels.

Variability of total phenytoin serum concentrations within elderly nursing home residents

Approximately 6% of all elderly nursing home residents receive phenytoin. Phenytoin concentrations are often measured to guide therapy. To evaluate the intraresident variability among multiple measurements of total phenytoin serum concentrations in nursing home residents. This was an observational study of 56 elderly (>or=65 years) nursing home residents from 32 nursing homes who had at least 3 phenytoin concentrations measured while on the same dose of phenytoin for at least 4 weeks and who were not taking any interfering concomitant medications. These were a subset of 387 elderly nursing home residents from 112 nursing homes across the United States who had total phenytoin concentration measurements between June 1998 and December 2000. The mean age was 80.1 years (range, 65 to 100 years) and 58.9% were women. The mean daily dose of phenytoin per resident was 4.9 +/- 1.5 mg/kg. Total phenytoin concentrations within an elderly nursing home resident varied as much as two- to threefold, even though there was no change in dose. The person with the smallest variability had a minimum concentration of 10.0 micro g/mL and a maximum of 10.4 micro g/mL. The person with the largest variability had a minimum concentration of 9.7 micro g/mL and a maximum of 28.8 micro g/mL. There is considerable variability in the total phenytoin concentrations in the elderly nursing home resident and measurement of a single total phenytoin concentration should not be used to guide treatment.

Synergistic Effect of Valproate Coadministration and Hypoalbuminemia on the Serum-Free Phenytoin Concentration in Patients With Severe Motor and Intellectual Disabilities

We investigated whether a combination of risk factors affects the free phenytoin (PHT) fraction by multiple regression analyses in 30 patients with severe motor and intellectual disabilities (SMID) with epilepsy. The risk factors analyzed were gender, age, total PHT concentration, albumin concentration, aspartate aminotransferase, alanin aminotransferase, serum creatinine, blood urea nitrogen, and antiepileptic drug concentrations. Serum levels of total and free PHT were measured by fluorescence polarization immunoassay. Free PHT fractions were between 7.2% and 17.3% (average 10.9%). Two factors, hypoalbuminemia and valproate (VPA) coadministratation with PHT, increased free PHT fraction, and a combination of these two markedly increased free PHT fraction. Patients with these double risk factors have a high risk of exceeding the therapeutic range of serum-free PHT concentration even if their total PHT concentration does not. Therefore, we should monitor free PHT concentration, especially in SMID patients with epilepsy, because they may have hypoalbuminemia and are treated with antiepileptic drug polytherapy and, moreover, cannot report adverse effects of the drugs.

Effect of albumin on phenytoin and tolbutamide metabolism in human liver microsomes: an impact more than protein binding.

The cytochrome P450 (P450)-dependent conversion of phenytoin (PHT) to p-hydroxy phenytoin (pHPPH), and tolbutamide (TLB) to 4-hydroxy tolbutamide (hydroxy-TLB), in human liver microsomes was studied in the presence of increasing concentrations (0-4%) of bovine serum albumin (BSA). Therefore, the free fraction (f(u)) of PHT and TLB varied. Whereas the f(u) of PHT (5 microM) decreased, an increase (3-fold), rather than a decrease in the pHPPH formation rate was observed when BSA (<1%) was present. The stimulation was attributed to a significant decrease in apparent K(m). The change, however, was diminished as the BSA concentration reached 4% (PHT f(u) = 0.2), in which the reaction velocity remained the same as that measured in the absence of BSA. Therefore, unchanged K(m) (16.2 +/- 0.7 microM) and V(max) (9.4 +/- 0.2 pmol/min/mg of protein) values were determined based on total PHT concentrations, whereas correction for f(u) led to an unbound K(m) (K(mu)) of approximately 3.2 microM. Similarly, the metabolism of TLB (50 microM) was enhanced (approximately 2-fold) in the presence of 0.25% BSA but remained only 35% of the control activity (no BSA) at 1% BSA. However, the remaining activity was higher (3-fold) than that determined with an equivalent free concentration of TLB (4 microM) calculated according to its f(u) (0.08). The difference became less significant when BSA concentration was 4% (f(u) < 0.02). Collectively, the results suggest a 2-fold effect of BSA on PHT and TLB hydroxylation: first, facilitation of the reactions via a decrease in K(m); second, a decrease in f(u) leading to a drop in reaction rate. For a given P450 reaction, therefore, the effect of BSA may depend upon enzyme affinity, catalytic capacity, and the extent of protein binding.

Pharmacokinetics of phenytoin following intravenous and intramuscular administration of fosphenytoin and phenytoin sodium in the rabbit.

The purpose of this study was to evaluate and compare plasma phenytoin concentration versus time profiles following intravenous (i.v.) and intramuscular (i.m.) administration of fosphenytoin sodium with those obtained following administration of standard phenytoin sodium injection in the rabbit. Twenty-four adult New Zealand White rabbits (2.1 +/- 0.4 kg) were anaesthetized with sodium pentobarbitone (30 mg/kg) followed by i.v. or i.m. administration of a single 10 mg/kg phenytoin sodium or fosphenytoin sodium equivalents. Blood samples (1.5 ml) were obtained from a femoral artery cannula predose and at 1, 3, 5, 7, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240 and 300 min after drug administration. Plasma was separated by centrifugation (1000 g; 5 min) and fosphenytoin, total and free plasma phenytoin concentrations were measured using high performance liquid chromatography (HPLC). Following i.v. administration of fosphenytoin sodium plasma phenytoin concentrations were similar to those obtained following i.v. administration of an equivalent dose of phenytoin sodium. Mean peak plasma phenytoin concentrations (Cmax) was 158% higher (P = 0.0277) following i.m. administration of fosphenytoin sodium compared to i.m. administration of phenytoin sodium. The mean area under the plasma total and free phenytoin concentration-time curve from time zero to 120 min (AUC(0-120)) following i.m. administration was also significantly higher (P = 0.0277) in fosphenytoin treated rabbits compared to the phenytoin group. However, there was no significant difference in AUC(0-180) between fosphenytoin and phenytoin-treated rabbits following i.v. administration. There was also no significant difference in the mean times to achieve peak plasma phenytoin concentrations (Tmax) between fosphenytoin and phenytoin-treated rabbits following i.m. administration. Mean plasma albumin concentrations were comparable in both groups of animals. Fosphenytoin was rapidly converted to phenytoin both after i.v. and i.m. administration, with plasma fosphenytoin concentrations declining rapidly to undetectable levels within 10 min following administration via either route. These results confirm the rapid and complete hydrolysis of fosphenytoin to phenytoin in vivo, and the potential of the i.m. route for administration of fosphenytoin delivering phenytoin in clinical settings where i.v. administration may not be feasible.

Evidence-based Implementation of Free Phenytoin Therapeutic Drug Monitoring

The majority of laboratories measure total phenytoin concentration for therapeutic drug monitoring. However, there are substantial interindividual variations in free phenytoin concentrations, the pharmacologically active component. We describe the process and data used to implement monitoring of free phenytoin only in an urban medical center. Over a 6-week period, total and free phenytoin concentrations were measured, clinical charts reviewed, and indications for alterations in the percentage of free phenytoin fraction were determined. Of the 189 phenytoin requests from 139 patients, 136 data points were analyzed. Free phenytoin concentrations were 6.8-35.3%, with 50% outside the expected range of 8-12%. Clinical indications likely responsible for variations were hypoalbuminemia, drug interactions, uremia, pregnancy, and age. Overall, 30% of patients demonstrated a discrepancy between therapeutic, subtherapeutic, or supratherapeutic concentrations between free and total phenytoin concentrations. The largest discordance (53%) occurred in the patient group with free phenytoin <8% or >12%. This study supports previous clinical findings that monitoring total phenytoin is not as reliable as free phenytoin as a clinical indicator for therapeutic and nontherapeutic concentrations. Thus, we recommend that therapeutic monitoring should use free phenytoin concentrations only.

Mathematical models to calculate fosphenytoin concentrations in the presence of phenytoin using phenytoin immunoassays and alkaline phosphatase.

Under certain circumstances, it is necessary to measure both fosphenytoin and phenytoin concentrations. We describe equations by which fosphenytoin concentrations can be calculated accurately by using phenytoin immunoassays. We supplemented aliquots of drug-free serum with fosphenytoin and measured the phenytoin equivalent concentrations (reading a) using fluorescence polarization immunoassay and a chemiluminescent assay. Then 10 microL of alkaline phosphatase (ALP) solution was added to the specimen, and after incubation for 5 minutes at room temperature, total phenytoin concentration was measured (reading b). ALP completely converts fosphenytoin to phenytoin in 5 minutes. Therefore, the delta reading (b-a) represents increased observed value due to complete conversion of fosphenytoin to phenytoin for a particular fosphenytoin concentration. By using the x-axis as the delta reading and the y-axis as the target fosphenytoin concentrations, we observed equations that can be used to calculate the concentration of fosphenytoin in the presence of phenytoin. To test the validity of our equations, we prepared 2 serum pools from patients receiving phenytoin and supplemented them with known concentrations of fosphenytoin. Then initial (reading a) and final (after addition of ALP and incubation, reading b) concentrations were measured by immunoassay. We can accurately predict fosphenytoin and phenytoin concentrations from the delta reading.

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.

Effect of heating human sera at a temperature necessary to deactivate human immunodeficiency virus on measurement of free phenytoin, free valproic acid, and free carbamazepine concentrations.

Minimizing the risk for infection to laboratory staff from a contaminated blood sample is a major safety goal in the clinical laboratory. One dangerous pathogen, the human immunodeficiency virus (HIV), can be deactivated by heating sera at 56 degrees C for 30 minutes. The authors previously reported that if serum was subjected to those conditions, the concentrations of the nine most commonly monitored drugs were not altered, whereas phenytoin and carbamazepine concentrations were reduced slightly. Monitoring free phenytoin, free valproic acid, and free carbamazepine concentrations is strongly recommended for patients with uremia, liver disease, and hypoalbuminemia. Because drug protein binding can be affected by temperature, the authors investigated the effect on free drug concentrations of sera heated to levels necessary for deactivation of the HIV virus. They measured total and free drug concentrations in serum pools prepared from patients receiving phenytoin, valproic acid, and carbamazepine. Serum pools were heated at 56 degrees C for 30 minutes and then brought to room temperature. The total and free drug concentrations were measured immediately after heating and then at 20- and 45-minute intervals. The concentrations of free phenytoin and free valproic acid were significantly higher after heat treatment. However, after equilibration of sera at room temperature for 20 minutes, the free concentrations of phenytoin were comparable to preheating values, although total phenytoin concentrations (Serum Separator Tubes) were reduced slightly. In contrast, free valproic acid concentrations did not return to the original levels even after 45 minutes. Free carbamazepine concentrations did not change even immediately after heating. However, total carbamazepine concentrations were reduced slightly when sera were heated in serum separator tubes (SST Tubes).

Pharmacology and pharmacokinetics of fosphenytoin

Fosphenytoin sodium, a phosphate ester prodrug of phenytoin, was developed as a replacement for parenteral phenytoin sodium. Unlike phenytoin, fosphenytoin is freely soluble in aqueous solutions, including standard i.v. solutions, and is rapidly absorbed by the i.m. route. Fosphenytoin is metabolized (conversion half-life of 8 to 15 min) to phenytoin by endogenous phosphatases. Therapeutic free (unbound) and total plasma phenytoin concentrations are consistently attained after i.m. or i.v. administration of fosphenytoin loading doses. Fosphenytoin has fewer local adverse effects (e.g., pain, burning, and itching at the injection site) after i.m. or i.v. administration than parenteral phenytoin. Systemic effects related to the CNS are similar for both preparations, but transient paresthesias are more common with fosphenytoin.

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.