Total Serum Phenytoin Concentrations Research Articles

Fosphenytoin dosing regimen including optimal timing for the measurement of serum phenytoin concentration in pediatric patients

IntroductionWe aimed to evaluate the pediatric fosphenytoin dosing regimen, including optimal timing for the measurement of total serum phenytoin concentration (CPHT). MethodsWe retrospectively investigated pediatric patients with status epilepticus or seizure clusters treated with fosphenytoin between April 2013 and March 2018. Two CPHT measurements were analyzed, one 2–4 h after the loading dose and another before the second dose. Individual pharmacokinetic parameters were estimated using the Bayesian method and were used to simulate CPHT. ResultsThe present study involved 12 pediatric patients; the loading dose of fosphenytoin was 22.1 (17.2–27.2) mg/kg. The CPHT was 13.4 (8.6–18.9) μg/mL 2–4 h after the loading dose. The CPHT estimated from individual pharmacokinetic parameters 12 and 24 h after the loading dose was 9.5 (6.7–14.2) and 5.8 (3.7–10.0) μg/mL, respectively. If fosphenytoin was administered at a loading dose of 22.5 mg/kg and a maintenance dose of 5 or 7.5 mg/kg (administered every 12 h, starting 12 h after the loading dose), then the CPHT on day 8 was estimated to be 5.74 (2.6–15.4) μg/mL at 5 mg/kg and 13.9 (5.7–31.0) μg/mL at 7.5 mg/kg. ConclusionsIn pediatric patients, a maintenance dose of fosphenytoin should be started 12 h after the loading dose, and a maintenance dose of 5–7.5 mg/kg/dose every 12 h may be better than every 24 h. We recommend measuring CPHT at 2 and 12 h after the loading dose to simplify and safely adjust the dosage in clinical practice.

Impact of Obesity on Fosphenytoin Volume of Distribution in Pediatric Patients.

The impact of body habitus on fosphenytoin pharmacokinetics is poorly understood in pediatric patients. This retrospective, single-center review examined differences in fosphenytoin volume of distribution (VD) between children with normal and obese body habitus. From 2013 to 2015, patients 2 to 18 years of age who received a loading dose of fosphenytoin were identified. Thirty-seven patients met inclusion criteria. Mean total serum phenytoin concentration was 25.3 ± 6.5 μg/mL in the nonobese group and 29.5 ± 7.6 μg/mL in the obese group ( P = .09). VD was not significantly different between obese and nonobese groups, 0.92 ± 0.26 L/kg and 0.97 ± 0.48 L/kg ( P = .76), respectively. In contrast to adult studies, these data suggest that fosphenytoin dose adjustments for obese children may be unnecessary.

Correlation of Free and Total Phenytoin Serum Concentrations in Critically Ill Patients.

Phenytoin is a common medication for seizure treatment and prophylaxis in the intensive care unit (ICU). The clinical utility of the Sheiner-Tozer equation for adjusting total phenytoin levels for hypoalbuminemia remains controversial. The purpose of this study was to evaluate the correlation of this formula in predicting phenytoin serum concentrations. A retrospective cohort study was conducted in the adult ICU between January 1, 2010, and June 21, 2013. Patients meeting the following study criteria were included: age ≥18 years, admission to the ICU, simultaneously drawn total and free serum phenytoin concentrations with albumin ≤48 hours of phenytoin draws. Study end points were the correlation as well as the level of agreement in the interpretation of the free and adjusted phenytoin concentrations using the Sheiner-Tozer formula in critically ill patients with hypoalbuminemia. A total of 238 patients were analyzed. Mean adjusted total phenytoin and free levels were 16.1 ± 8.1 and 1.5 ± 0.8 µg/mL, respectively (r = 0.817; P < 0.001). Absolute agreement with level interpretation between adjusted total phenytoin and free levels was 77% (κ = 0.633; P < 0.001). Adjusted phenytoin serum concentrations more frequently overestimated the free level. There is a significant correlation between free and adjusted total phenytoin levels using the Sheiner-Tozer equation in critically ill patients. However, disagreement was noted with interpretation, primarily because of the adjusted concentration overestimating the free level. This imprecision may lead to inaccurate decision making regarding the management of phenytoin in this patient population. Thus, free phenytoin levels should be utilized.

G335(P) Phenytoin dosing and serum concentrations in paediatric patients requiring 20 mg/kg intravenous loading dose

AimPhenytoin’s loading dose for refractory tonic-clonic seizures in children was changed from 18 mg/kg to 20 mg/kg in January 2011 to reduce the theoretical risk of miscalculation. Phenytoin has complex...

Phenytoin Loading Doses in Adult Critical Care Patients: Does Current Practice Achieve Adequate Drug Levels?

Phenytoin is regularly employed in the critically ill for prophylaxis against or treatment of seizure disorders. No prior studies have examined current dosing practices in an Australasian intensive care unit (ICU) setting. The aims of this study were to: a) describe the adequacy of contemporary dosing in respect to free and total serum phenytoin concentrations; b) identify factors associated with therapeutic drug concentrations; and c) examine the accuracy of predictive equations that estimate free concentrations in this setting. All patients receiving a loading dose of phenytoin in a tertiary-level ICU were eligible for enrolment; 53 patients were enrolled in the study. Serum samples to determine free and total phenytoin concentrations (measured by high performance liquid chromatography) were then drawn prior to the following dose. Free concentrations below the recommended target (<1 mg/l) were considered as suboptimal. The most common indication for phenytoin loading was traumatic brain injury (49%) and the mean administered dose was 14.5 (3.66) mg/kg. Twenty-six patients (49%) had suboptimal trough free concentrations, although this subgroup was significantly heavier and therefore received a lower per kilogram dose (12.8 [3.1] vs 16.3 [3.4] mg/kg, P=0.001). In multivariate analysis, larger weight adjusted doses (P=0.018), higher albumin concentration (P=0.034) and receiving phenytoin for an indication other than seizure (P=0.035), were associated with a greater likelihood of adequate concentrations. In conclusion, phenytoin dosing remains complex in critically ill patients, although lower per kilogram loading doses are strongly associated with free concentrations below the desired target.

Total Phenytoin concentration is not well correlated with active free drug in critically-ill head trauma patients.

Objective:Phenytoin is an antiepileptic drug used widely for prophylaxis and treatment of seizure after neurotrauma. Phenytoin has a complex pharmacokinetics and monitoring of its serum concentrations is recommended during treatment. Total phenytoin concentration is routinely measured for monitoring of therapy. In this study, we evaluated the correlation between phenytoin total and free concentrations in neurotrauma critically-ill patients to determine whether the phenytoin total concentration is a reliable predictor of free drug, which is responsible for the therapeutic effects.Methods:A total of 40 adult head trauma patients evaluated for free (unbound) and total serum phenytoin concentrations. Patients were divided into two groups. Group A consists of 20 unconscious patients with severe head injury under mechanical ventilation and Group B consists of 20 conscious self-ventilated patients. Correlation and agreement between total and free phenytoin plasma concentrations were analyzed.Findings:Pearson correlation analysis and Bland-Altman test showed weak to moderate correlation (r = 0.528) and poor agreement between free and total phenytoin concentrations in patients with severe trauma and higher Acute Physiology And Chronic Health Evaluation II (APACHE II) scores (Group A) and good correlation (r = 0.817) and moderate agreement in patients with mild to moderate trauma and lower APACHE II scores (Group B).Conclusion:Our results indicated that total phenytoin serum concentration is not a reliable therapeutic goal for drug monitoring in severely-ill head trauma patients even in the absence of hypoalbuminemia, renal and hepatic failure. It seems justifiable to measure free phenytoin concentration in all severely ill neurotrauma patients.

Variability of Total Phenytoin Serum Concentrations Within Elderly Nursing Home Residents

Variability of Total Phenytoin Serum Concentrations Within Elderly Nursing Home Residents

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

Variability of total phenytoin serum concentrations within elderly nursing home residents

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.

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.

Phenytoin pharmacokinetics: before and after folic acid administration.

Phenytoin (PHT) exhibits linear and Michaelis-Menten pharmacokinetics. PHT decreases serum folate; the vitamin folic acid (FA) is hypothesized to be a cofactor in the metabolism of PHT. The depletion of serum folate may explain the unpredictability of measured total serum PHT concentrations and time to steady state as compared with the Michaelis-Menten predictive calculations. We examined PHT pharmacokinetics before and after FA supplementation in 13 healthy male volunteers. The study was divided into two phases. Phase I determined V(max) (mg/day) and Km (micrograms/ml) of PHT to calculate PHT doses needed for the second phase. Phase II was a four-way cross-over study to examine the effect of 1 and 5 mg FA on total serum PHT concentrations 1 microgram/ml less and 5 micrograms/ml greater than the subject's Km, Km - 1 and Km + 5, respectively. Predicted versus measured total serum PHT concentrations, t90% (days to steady state), and the effect of FA were calculated for Km - 1 and Km + 5 before and after 1 or 5 mg FA. The measured total serum PHT concentration was always greater than the calculated concentration (p less than 0.05), and t90% was always longer than the calculated t90% (p less than 0.05) for Km - 1 before FA (all subjects decreased serum FA); the same was observed for Km + 5. If folate is assumed to be a cofactor in PHT metabolism, these results are expected, because depletion of the vitamin would indicate less folate to drive the metabolism of PHT, resulting in higher total serum PHT concentrations and longer time to reach steady state.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Serum Separator Tubes on Free and Total Phenytoin and Carbamazepine Serum Concentrations

The effect of serum separator tubes (SSTs) on free and total serum phenytoin and carbamazepine concentrations was determined by comparing standard no-additive tubes with SSTs (Becton Dickinson SST and Terumo Autosep). The influence of time prior to centrifugation, sample volume, and initial drug concentration on the effects were also studied. Results were analyzed using repeated measures two-way analysis of variance with tube type and either time, sample volume, or concentration as main effects. The most significant reductions noted were with Becton Dickinson SSTs in free and total serum phenytoin and total carbamazepine concentrations, where all reductions were less than 10%. The only factor to significantly influence extent of reduction was the effect of time on total serum phenytoin concentration in Becton Dickinson SSTs. Terumo Autosep tubes caused no major reductions in free or total phenytoin or carbamazepine serum concentrations. Autosep tubes should provide accurate measurements of total and free serum phenytoin and carbamazepine concentrations. With Becton Dickinson SSTs, the reductions noted in free and total phenytoin and total carbamazepine concentrations were not large enough to preclude their clinical use. Becton Dickinson SSTs should not be used for determining free or total phenytoin or total carbamazepine concentrations for purposes of research.

Effect of Acute and Chronic Terfenadine on Free and Total Serum Phenytoin Concentrations in Epileptic Patients

Terfenadine is a unique H1-receptor antagonist devoid of adverse central nervous system (CNS) effects. Terfenadine is highly protein bound and has been shown to stimulate hepatic microsomal enzymes, making an interaction with phenytoin (PHT) possible. After assuring constant PHT levels for 7 days, 12 epileptic patients were studied with PHT alone, after a single daily dose of terfenadine (60 mg twice daily), and again after 2 weeks of chronic terfenadine therapy. Samples for PHT were drawn over 24 h, and urine was collected for determination of the PHT metabolite 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH). The pharmacokinetic parameters calculated for total and free PHT and HPPH were area under the time concentration curve (AUC), the maximum serum concentration (Cmax), the minimum serum concentration (Cmin), and the percentage of fluctuation between maximum and minimum concentrations. A factor analysis was used to clarify interrelationships. Five dependent variables were found to represent the data. These were assessed by multi-variate analysis of variance (MANOVA); p less than 0.05 was considered significant. No significant differences were observed for any of the parameters for the acute or chronic effects of terfenadine. We conclude that terfenadine does not interfere with PHT.

Decrease of serum folates in healthy male volunteers taking phenytoin.

The effect of phenytoin (PHT) on serum folate and the effect of additional oral folic acid (FA) on serum folate during continued treatment with PHT were studied in 13 healthy male subjects 20-35 years of age. The study was divided into two phases: Phase I determined Vmax (mg/kg/day) and Km (microgram/ml) of PHT in order to calculate the PHT doses needed for the second phase. Phase II was a four-way cross-over study to examine the effect of 1 and 5 mg FA on total serum PHT concentrations 1 microgram/ml less and 5 micrograms/ml greater than the subject's Km, Km-1 and Km+5, respectively. Both phases examined the effect of PHT on serum folate. In Phase I, serum folate decreased by a mean and standard deviation of 42.15 +/- 21.44% after an average of 24.15 +/- 5.63 days of PHT administration, with a mean steady-state total serum PHT concentration of 8.45 +/- 2.70 micrograms/ml. Mean percentage decreases in serum folate before the addition of 1 and 5 mg FA in Phase II were 12.80 +/- 31.45% and 23.24 +/- 21.24% for Km-1 and Km+5, respectively. The average numbers of days of PHT administration and total serum PHT concentrations before FA administration were 9.52 +/- 3.34 and 15.84 +/- 7.02 days, and 2.60 +/- 2.18 and 8.64 +/- 3.44 micrograms/ml, for Km-1 and Km+5, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Protein binding of phenytoin and lidocaine in pediatric patients with type I diabetes mellitus.

We evaluated serum protein binding of phenytoin and lidocaine, the extent of albumin and hemoglobin glycation, and alpha-1-acid glycoprotein concentrations in 47 children and adolescents (9-17 years) with type I diabetes mellitus (DM). Serum was incubated with phenytoin (n = 47) and lidocaine (n = 32) to yield total concentrations of 19.4 +/- 1.34 and 4.6 +/- 0.5 mg/l, respectively. A serum ultrafiltrate was prepared from an aliquot of each sample by membrane centrifugation. Total and free concentrations of phenytoin (free fraction 8.3 +/- 1.0%) and lidocaine (free fraction 25.8 +/- 11.6%) were determined using a fluorescence polarization immunoassay technique. A linear relationship (r = 0.63, p = 0.0001, y = 40.1 + [-0.2x]) was also found between the alpha-1-acid glycoprotein concentration (68.5 +/- 20.9 mg%, range 47.2-134.7 mg%) and lidocaine-free fraction (n = 32). No relationship existed between the extent of glycated albumin and the lidocaine-free fraction, in contrast to the linear correlation (r = 0.49, p = 0.0005, y = 3.7 + 0.4x) found between the extent of glycated albumin and the free fraction of phenytoin in serum (n = 47). A similar correlation (r = 0.49, p = 0.014, y = 3.7 + 0.3x) was found between glycated albumin (%) and the phenytoin-free fraction (3.9 +/- 0.9%) when examined in a separate (n = 17) set of patient samples spiked to contain a total serum phenytoin concentration of 32.6 +/- 1.4 (range 29.4-35.7) mg/l. Our data demonstrate a predictable increase in the free fraction of phenytoin as the extent of albumin glycation increases in pediatric patients with type I DM who are in poor glycemic control. This relationship was not found for lidocaine, a representative basic compound. These findings suggest that glycation of albumin alters the binding of phenytoin in children and adolescents with type I DM.

Utilization of Km for Phenytoin Dosage after Folate Addition to Patient Regimen

Phenytoin decreases serum and red blood cell folates in 50% of the patients on the anticonvulsant. The supplementation of folic acid changes the disposition of phenytoin, a drug that exhibits Michaelis-Menten kinetics. In a retrospective study at the Veterans Administration Medical Center, seven adult male folate-deficient epileptic patients on phenytoin alone and compliant with the anticonvulsant were supplemented with 1 mg oral folic acid. Before and after the addition of the vitamin, Vmax and Km were calculated for phenytoin. With folic acid, the total serum phenytoin concentration decreased significantly by an average of 22.6 +/- 13.0%. The Km decreased significantly from 6.7 +/- 1.1 to 4.1 +/- 1.5 micrograms/ml. The Vmax remained unchanged. It is hypothesized that folic acid is a cofactor in the metabolism of phenytoin. A cofactor would be expected to alter the affinity (Km) of the enzymes for phenytoin with no change in the liver's total capacity (Vmax) to metabolize phenytoin. This retrospective study in seven male epileptic patients is a convincing argument for the hypothesis.

Identifying patients who might benefit from free phenytoin monitoring.

Guidelines for measuring free drug concentrations in serum have become necessary due to the easy availability of these assays as a result of the introduction of commercial kits. The present study was performed to identify patients or groups of patients in whom the serum free phenytoin fraction varied from normal, such that they might benefit from measurement of serum free phenytoin. Three hundred fourteen samples submitted for routine phenytoin analysis were studied by enzyme-modified immunoassay technique (EMIT). Thirty-eight patients on phenytoin monotherapy and without other factors thought to affect protein binding of this drug had a mean (+/- SD) free phenytoin fraction of 9.8 +/- 1.8% of total concentration (mean serum albumin concentration 43.4 +/- 3.9 g/L). The free fraction was elevated by administration of comedications which are themselves highly protein bound, and in those patients who were hypoalbuminaemic (serum albumin less than 30 g/L). The groups studied were not mutually exclusive, but stepwise regression analysis showed that other factors known to affect serum albumin (e.g., age greater than 65 years, liver or renal disease, or pregnancy) did not, in themselves, produce a significant effect on free phenytoin fraction. Similarly, an elevated total serum phenytoin concentration was not a significant factor in producing an elevation in free phenytoin fraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Alteration of phenytoin binding by glycosylation of albumin in IDDM.

We measured glycosylated albumin and hemoglobin and serum protein binding of phenytoin in 57 children and adolescents with insulin-dependent diabetes mellitus (IDDM). Serum was incubated with phenytoin to yield concentrations of 15 and 25 mg/L, and a serum ultrafiltrate was prepared from an aliquot of each sample. We observed a linear correlation between glycosylated albumin and the free fraction of phenytoin at serum phenytoin concentrations of 15 mg/L (r = .35, P = .03) and 25 mg/L (r = .40, P = .003). A better correlation existed between the free fraction of phenytoin and total albumin concentrations for both serum concentrations (r = .45, P = .005 for 15 mg/L; r = .56, P = 10-5) for 25 mg/L), whereas the best linear correlation resided between the free fraction of phenytoin and the concentration of nonglycosylated albumin (r = .54, P = .0005 for 15 mg/L; r = .63, P less than 10(-6) for 25 mg/L). There was no correlation between the free fraction of phenytoin and the concentration of glycosylated albumin. Incubation of solutions of glycosylated and nonglycosylated albumin demonstrated significantly lower binding to the glycosylated fraction (P = 8.1 X 10(-6)). These results indicate that glycosylation of albumin diminishes the affinity of the phenytoin binding site on albumin. This alteration may have clinical significance in that it may alter the disposition of phenytoin in patients with IDDM and produce free phenytoin serum concentrations that are not accurately reflected by total serum phenytoin concentrations.