Plasma Phenytoin Research Articles

Pharmacokinetic interactions between erythromycin, clarithromycin, roxithromycin and phenytoin in the rat.

The effects of the macrolide antibiotics, erythromycin, clarithromycin and roxithromycin, on the pharmacokinetic profile of phenytoin were studied in rats. Animals were injected with phenytoin (100 mg/kg, i.p.) daily for 4 days and then they were given phenytoin (20 mg/kg, i.p.) alone or the same dose of phenytoin together with erythromycin (50 mg/kg, i.p.), clarithromycin (50 mg/kg, i.p.) or roxithromycin (50 mg/kg, i.p.). In another set of experiments, the same protocol was followed except that erythromycin (100 mg/kg), clarithromycin (100 mg/kg) and roxithromycin (100 mg/kg) were given by the oral route. The concentrations of phenytoin in plasma were determined using a high-performance liquid chromatographic method. The area under the curve the maximum plasma concentration and the elimination half-life (t1/2) of phenytoin were significantly (p < 0.05) increased by the macrolides. In addition, the macrolides significantly (p < 0.05) reduced the level of hepatic cytochrome P-450 in the rats. These results suggest that a potentially harmful drug-drug interaction may occur if phenytoin is administered concurrently with erythromycin, clarithromycin or roxithromycin.

Elevated Plasma Alpha1-Acid Glycoprotein Levels

This study was designed to investigate the relationships among anticonvulsant therapy, plasma alpha 1-acid glycoprotein (AAG) levels, and resistance to vecuronium blockade. Thirty-one patients scheduled for routine neurosurgery were included in the study. The patients were treated (TG; n = 20) with phenytoin (n = 15) and/or carbamazepine (n = 4) and/or phenobarbital (n = 3) for > or = 6 days or were left untreated (UG; n = 11, control group). TG patients were further assigned to one of two subgroups according to the plasma anticonvulsant level measured the day before surgery and found to be within (TGW, n = 10) or below (TGB, n = 10) the therapeutic range. Finally, the 31 patients were divided into two more groups according to their plasma AAG levels: higher than (HAAG, n = 17) or within (NAAG, n = 14) the normal range (25-94 mg dl-1). Anesthesia was induced and maintained with propofol and sufentanil. Muscle relaxation was obtained with vecuronium 0.1 mg kg-1. A train-of-four (TOF) stimulation mode at 2 Hz was applied to the ulnar nerve every 15 s, and neuromuscular transmission was assessed using a TOF-Guard accelograph monitor. Plasma AAG concentrations (means +/- SEM) were 103.7 +/- 7.6 mg dl-1 in TG, 80.7 +/- 6.7 mg dl-1 in UG, 95.9 +/- 13.2 mg dl-1 in TGW, 111.6 +/- 7.6 mg dl-1 in TGB. 114.9 +/- 7.4 mg dl-1 in HAAG, and 71.4 +/- 3.8 mg dl-1 in NAAG groups. The differences in plasma AAG concentrations between UG and TG and between HAAG and NAAG groups were statistically significant. No significant relationship was found between plasma AAG levels and phenytoin concentrations (r = -0.26). The time (mean +/- SEM) to recovery of T1 to 25% of control was significantly shorter in TG (28.2 +/- 1.4 min) than in UG (42.2 +/- 3.1 min) but did not differ significantly according to the plasma anticonvulsant level (27.3 +/- 2.0 min in TGW; 29.1 +/- 1.9 min in TGB) and the plasma AAG level 31.7 +/- 1.9 min in HAAG; 35.3 +/- 3.3 min in NAAG). The time for the TOF ratio to recover to 25% yielded similar profiles and statistical significance levels: TG, 32.9 +/- 2.2 min; UG, 51.2 +/- 4.0 min; TGW, 35.0 +/- 3.9 min; TGB, 30.7 +/- 1.8 min; HAAG, 38.1 +/- 3.1 min; NAAG, 42.0 +/- 4.1 min. We conclude that anticonvulsant therapy induces an increase in plasma AAG independently of the plasma anticonvulsant level. However, duration and recovery of vecuronium blockade do not differ according to plasma AAG levels. Consequently, elevated AAG does not contribute to the resistance to vecuronium blockade induced by anticonvulsants.

Infant monkey hyperexcitability after prenatal exposure to antiepileptic compounds.

A monkey (Macaca fascicularis) model was previously used to assess infant hyperexcitability after prenatal exposure to phenytoin (PHT), stiripentol (STP) or PHT+STP. To explore this issue further, we studied additional monkey infants in those groups, as well as groups prenatally exposed to carbamazepine (CBZ) in monotherapy (n = 5) or CBZ+STP polytherapy (n = 10). The drug-exposed groups were compared with a group of control infants (n = 10) for whom procedures were matched except that there was no prenatal drug exposure. All adult female monkeys were equipped with tether systems and stomach catheters so that drug administration (or water for controls) could be initiated before they were mated and continued throughout pregnancy. During pregnancy, PHT, STP, and CBZ plasma levels were maintained between 4-12, 4-10, and 1-6 micrograms/ ml, respectively (for both monotherapy and polytherapy). At birth, infants were separated from mothers and transferred to the University of Washington's (Seattle, WA, U.S.A.) Infant Primate Research Laboratory (IPRL) for postnatal care and follow-up testing. During tests of recognition memory administered between 2 weeks and 3 months of age, infants were rated on a hyperexcitability scale. Previously reported data indicated that infants prenatally exposed to PHT, in monotherapy or polytherapy with STP, were at increased risk for hyperexcitability (screeching, refusing to attend to stimuli, lack of visual orientation). This was not the case for infants prenatally exposed to STP monotherapy. Our results confirm previous findings and also demonstrate that infants prenatally exposed to CBZ or CBZ+STP, like controls, are not hyperexcitable during testing.

Phenytoin pretreatment prevents hypoxic-ischemic brain damage in neonatal rats

This study was performed to investigate whether the anticonvulsant phenytoin has neuroprotective effect in a model of hypoxia-ischemia with neonatal rats. The left carotid artery of each rat was ligated, followed by 3 h of hypoxic exposure (8% O2) in a temperature-regulated environment (36°C). Two weeks later, brain damage was assessed by measuring loss of brain hemisphere weight. Phenytoin had no effect on body temperature or plasma glucose, but attenuated brain damage in a dose-dependent manner (3, 10, and 30 mg/kg i.p.) when administered before the hypoxic episode. Phenytoin administered during or after hypoxia did not alter hypoxic brain damage significantly. A parallel experiment using histological examination of frozen brain sections demonstrated less brain infarction after phenytoin treatment (30 mg/kg i.p.). In an additional experiment measuring breakdown of an endogenous brain calpain substrate, spectrin, phenytoin treatment reduced this measure of early cellular damage. Our results indicate that pretreatment with phenytoin is neuroprotective at a plasma phenytoin concentration of approximately 12 μg/ml. These results are consistent with the hypothesis that blockade of voltage-dependent sodium channels reduces brain damage following ischemia.

Phenytoin pretreatment prevents hypoxic-ischemic brain damage in neonatal rats

This study was performed to investigate whether the anticonvulsant phenytoin has neuroprotective effect in a model of hypoxia-ischemia with neonatal rats. The left carotid artery of each rat was ligated, followed by 3 h of hypoxic exposure (8% O 2) in a temperature-regulated environment (36°C). Two weeks later, brain damage was assessed by measuring loss of brain hemisphere weight. Phenytoin had no effect on body temperature or plasma glucose, but attenuated brain damage in a dose-dependent manner (3, 10, and 30 mg/kg i.p.) when administered before the hypoxic episode. Phenytoin administered during or after hypoxia did not alter hypoxic brain damage significantly. A parallel experiment using histological examination of frozen brain sections demonstrated less brain infarction after phenytoin treatment (30 mg/kg i.p.). In an additional experiment measuring breakdown of an endogenous brain calpain substrate, spectrin, phenytoin treatment reduced this measure of early cellular damage. Our results indicate that pretreatment with phenytoin is neuroprotective at a plasma phenytoin concentration of approximately 12 μg/ml. These results are consistent with the hypothesis that blockade of voltage-dependent sodium channels reduces brain damage following ischemia.

Drug interaction profile of topiramate.

In separate studies, potential pharmacokinetic interactions of topiramate (TPM) with phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA) were evaluated. TPM was added to the baseline antiepileptic drug (AED) at a dosage of up to 800 mg/day, after which the baseline drug was discontinued, when possible. Addition of TPM produced no change in plasma levels of CBZ or CBZ epoxide (CBZ-E). Modest increases in PHT plasma levels in six of 12 patients treated with PHT and TPM, and a small mean decrease in VPA levels noted in patients receiving VPA with TPM, were considered unlikely to require adjustments in the dosage of the concomitant AED when TPM is added or discontinued. When patients were changed from concomitant therapy with PHT or CBZ to TPM monotherapy, TPM clearance was reduced by approximately 50%, suggesting that an adjustment in TPM dose may be required when PHT or CBZ is discontinued from TPM-treated patients. A slight increase in plasma TPM levels during monotherapy compared to concomitant therapy with VPA was considered clinically insignificant and not likely to require TPM dosage adjustment. In another study, oral clearance of digoxin was slightly increased when TPM was added, resulting in a small decrease in peak plasma levels of digoxin. In vitro studies conducted to date on a number of specific cytochrome P450 isoforms show an effect of TPM only on the CYP2Cmeph isoform. The risk for clinically meaningful changes in plasma levels of traditional AEDs when TPM is added to or discontinued from concomitant regimens appears to be minimal. However, adjustments in TPM dosages are likely to be needed when potent enzyme inducers, such as PHT or CBZ, are added or discontinued. TPM has a relatively low propensity for clinically significant drug interactions, and its pharmacokinetic and drug interaction profiles represent a clear advance over those of the traditional AEDs.

Plasma and saliva concentrations of phenytoin and 5-(4-hydroxyphenyl)-5-phenylhydantoin in relation to the incidence and severity of phenytoin-induced gingival overgrowth in epileptic patients.

This study examined the relationships between plasma and saliva concentrations of phenytoin and 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH), the major metabolite of phenytoin in man, and the prevalence and severity of gingival overgrowth. Thirty-six adult epileptic patients who had been receiving phenytoin for greater than 6 months without a recent change in dosage were assessed for signs of periodontal disease and gingival overgrowth. Plasma and saliva samples were analyzed by high performance liquid chromatography for the determination of phenytoin and HPPH concentrations. Seventeen patients demonstrated clinically significant gingival over-growth (responders; overgrowth index > or = 30%). There were significant correlations between the gingival overgrowth index and both the papillary bleeding index (r = 0.495; P < 0.005) and probing depth (r = 0.632; P < 0.005). The plaque index correlated with the papillary bleeding index (r = 0.420; P < 0.05) and the probing depth (r = 0.301; P < 0.005), but not with the gingival overgrowth index. The extent of gingival overgrowth did not correlate significantly with either plasma or saliva concentrations of phenytoin or HPPH. Mean plasma and saliva concentrations of phenytoin and HPPH did not differ significantly between non-responders and responders, nor did the mean plaque index. The mean papillary bleeding index (32.5 +/- 21.2 vs. 63.8 +/- 37.7; P < 0.01) and mean probing depth (12.4 +/- 14.4% vs. 35.9 +/- 25.3%; P < 0.02) were significantly greater in the responders. This study found no evidence of a relationship between phenytoin or HPPH concentrations in plasma or saliva and the extent, or prevalence of phenytoin-induced gingival overgrowth. Further studies with larger populations may be necessary to establish the relationship, if any, between phenytoin or HPPH levels and gingival overgrowth.

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.

Liquid chromatographic assay in plasma of one of the members of a new series of anticonvulsants: d,l-3-hydroxy-3-ethyl-3-phenylpropionamide

A method for the simultaneous determination of HEPP ( d,l-3-hydroxy-3-ethyl-3-phenylpropionamide), a member of a new homologous series of phenylamide-derivative anticonvulsants, with six other antiepileptic drugs (ethosuximide, primidone, phenobarbital, phenytoin, carbamazepine and clonazepam) in plasma by high-performance liquid chromatography is described. These drugs are extracted from plasma by adding an equal volume of acetonitrile. An aliquot of the extract is then injected on a reversed-phase column with a acetonitrile-methanol-phosphate buffer mobile phase. The total time required for the whole analytical process, including the plasma pretreatment and chromatography, is approximately 30 min. The assay method is simple, rapid and reproducible, and therefore considered suitable for routine use in clinical investigations monitoring HEPP simultaneously with common antiepileptic drugs.

Diltiazem and verapamil elevate plasma phenytoin concentrations in the rat

The effects of the calcium channel blockers, diltiazem and verapamil on the pharmacokinetics of phenytoin were investigated in rats. Animals were given phenytoin alone or phenytoin together with either diltiazem or verapamil and the plasma samples were collected at different time intervals. The concentration of phenytoin was measured using a high performance liquid chromatographic method (HPLC). Diltiazem and verapamil significantly ( p < 0.05) increased the area under the curve (AUC), the maximum plasma concentration ( C max) and elimination half+life ( t 1:2) of phenytoin. These results suggest that a potentially harmful drug-drug interaction may occur if phenytoin is administered concurrently with either diltiazem or verapamil.

病棟活動の質的向上への試み（第３報） 癌化学療法施行時における血中および脳脊髄液中のフェニトインとフェノバルビタールの濃度変化

A clinical pharmacy servise was performed by the pharmacist using therapeutic drug monitoring (TDM) of phenytoin (PH) and phenobarbital (PB) for a patient with gliobrastoma during cancer chemotherapy. The cancer chemotherapeutic regimen with intraarterial or intravenous infusion was performed six times, which included a short-interval chemotherapy (from the first treatment to the third one with 1 day interval) and a long-interbal chemotherapy (from the fourth treatment to the sixth one with about 2-month interval), to the patient chronically administered with PH and PB.In each chemotherapy, total and free concentrations of PH and PB in plasma or CSF did not change. In the short-interval chemotherapy, total and free, concentrations of PH and PB in plasma or CSF decreased sharply. The free concentrations of PH and PB in plasma or CSF were equal. On the other hand, the total and free concentrations of PH and PB in plasma or CSF increased gradually in the long-interval chemotherapy. Especially, the total concentration of PH in CSF at the sixth treatment increased to 3 times larger than that at the first treatment. Total protein CSF increased from 122.7 mg/ml to 760.0mg/ml. The bound concentrations of PH in CSF correlated with the total protein in CSF, but the free concentrations of PH and PB in plasma and CSF did not change. The monitoring of PH and PB during the cancer chemotherapy was necessary to minimized the seizure for decreased level of anticonvulsant.

The pharmacokinetics of phenytoin in gingival crevicular fluid and plasma in relation to gingival overgrowth

The aim of this study was to determine whether phenytoin (PHT) could be detected in gingival crevicular fluid (GCF), and to relate its concentration to both plasma level and degree of gingival overgrowth. 23 patients medicated with phenytoin for at least 6 months were clinically examined for signs of periodontal disease and gingival overgrowth. 12 patients out of these demonstrated clinically significant overgrowth and their plaque scores and gingival inflammation were greater than for the non-overgrowth group (p < 0.001). Phenytoin concentrations were determined by high performance liquid chromatography, and was detected in GCF. There was a significant correlation between the GCF and plasma phenytoin concentrations (p < 0.05), but it was not related to the extent of gingival overgrowth. Inflammation increased the GCF volume, but was not a determinant of GCF phenytoin concentration. It is concluded that effusion of phenytoin into GCF is regulated by the plasma levels of the drug, but its concentration in GCF is not related to the incidence of gingival overgrowth.

Simultaneous determination of plasma phenytoin and its primary hydroxylated metabolites in carbon tetrachloride-intoxicated rats by high-performance liquid chromatography

We have developed a simple and sensitive method for the simultaneous determination of phenytoin (PHT), 5( p-hydroxyphenyl)-5-phenylhydantoin ( p-HPPH) and 5-( m-hydroxyphenyl)-5-phenylhydantoin ( m-HPPH) in rat plasma by high-performance liquid chromatography. The three substances were separated on a reversed-phase column (5 μm TSK gel ODS-80TM, 250 mm × 4.6 mm I.D.) using acetonitrile-0.008 M NaH 2PO 4 (pH 6) (35:65, v/v) as a mobile phase at a flow-rate of 0.8 ml/min. Absorbance was monitored at 215 nm. The quantification limit was 50 ng/ml for each of PHT, m-HPPH and p-HPPH. The mean recoveries for DPH, m-HPPH and p-HPPH from plasma were 95.6±3.6, 94.5±4.2 and 98.6±2.9%, respectively.

Case Report

We report a clinically relevant suspected interaction between acyclovir and the antiepileptic drugs phenytoin (PHT) and valproic acid (VPA). In a child receiving PHT and VPA therapy, a 6-day acyclovir treatment reduced PHT and VPA plasma concentrations to subtherapeutic values. This probably worsened both clinical status and electroencephalographic recordings observed in this patient. We suggest that the interaction occurs at gastrointestinal level with a reduction of PHT and VPA oral bioavailability during antiviral treatment.

Phenytoin Causes a Rapid Increase in 6β‐Hydroxycortisol Urinary Excretion in Humans—A Putative Measure of CYP3A Induction

This study was conducted in eight healthy volunteers to assess the time course of induction of cytochrome P‐450 by phenytoin. Subjects received 200mg of phenytoin every 8h for 11 doses and 100mg every 8h for 8 doses. Trough concentrations of phenytoin in plasma were measured by HPLC. Urine samples were collected between 08:00 and 12:00 on days minus; 1, 1, 2, 3, 4, 5, and 7. Urinary concentrations of 6β‐hydroxycortisol (6β‐OHC) and cortisol (C) were determined by HPLC and were reported as a ratio (6β‐OHC/C); this ratio is a marker for the 3A isozyme family of cytochrome P‐450 (CYP3A). Mean plasma phenytoin concentrations on day 7 were 15.4 ± 7.20 µg/mL. Mean 6β‐OHC/C ratios increased by a factor of 2.37 from baseline during the course of the study. Values for the ratios on days 4, 5, and 7 were significantly higher than baseline by Dunnett's test (one‐sided) (p<0.05); the day 3 value was borderline statistically significant. These results show that phenytoin rapidly induces the activity of the CYP3A family of isozymes, with effects apparent within 48h after the initiation of phenytoin therapy.

Phenytoin and Plasmapheresis

The effect of plasmapheresis (PP) on total and free phenytoin clearance is reported. An obese patient with the diagnosis of thrombotic thrombocytopenic purpura (TTP) was treated with PP. Twelve episodes of PP, having exchange volumes of 1.5-2.25 times the plasma volume with a mean +/- SD 7.7 +/- 0.8 L of plasma removed, were studied. A significant (p < 0.05) difference was observed with a mean change in plasma phenytoin concentrations from pre- to end-PP of 7.32 +/- 2.5 mg/L compared to 1.98 +/- 0.7 mg/L observed pre-PP to 1 h post-PP. These values corresponded to 48.4 +/- 11.6 and 15.0 +/- 6.7% decreases in phenytoin concentrations at the two aforementioned time periods. To prevent misinterpretation of plasma phenytoin concentrations, samples should not be obtained for at least 2 h after PP.

Phenytoin pharmacokinetics after intravenous administration to patients receiving enteral tube feeding

Serial plasma samples were collected after administration of 13 intravenous doses of phenytoin to 11 patients with head injury; 5 to patients who had been receiving enteral feeds for less than 5 days (group 1), and 8 to patients who had been receiving enteral feeds for longer than 5 days (group 2). Average plasma phenytoin concentrations were higher in group 1 than in group 2 (p=0.003). The median intravenous study dose was the same (300 mg) in both groups (p=0.1 7). Group 2 received slightly higher doses expressed as mg/kg (median of 5.45 mg/kg compared to 4.29 mg/kg in group 1, p=0.21). Phenytoin was more rapidly eliminated following intravenous dosing in patients receiving long-term enteral feeding.Vmax was higher in group 2 than in group 1 (medians, 709versus 394 mg/day) andKm smaller (medians, 2.5versus 3.9 mg/l), but volume of distribution was similar in both groups (p=0.88). The kinetic parameters of phenytoin in group 1 were similar to previously published population pharmacokinetic parameters. In order to maintain phenytoin concentrations adequate for seizure prophylaxis in patients receiving longterm enteral feeding it would be advisable to decrease the dosing interval as well as increasing the phenytoin dose when the drug is administered intravenously.

Ciprofloxacin may reduce plasma phenytoin concentrations

Ciprofloxacin may reduce plasma phenytoin concentrations

Effect of Ciprofloxacin on the Pharmacokinetics of Multiple-Dose Phenytoin Serum Concentrations

We performed this study to determine if an interaction exists during the co-administration of ciprofloxacin with phenytoin. Seven healthy volunteers received oral phenytoin, 200 mg/day, as a single dose for 10 days. On day 9, phenytoin blood sampling was performed at times 0, 1, 2, 4, 6, 8, 10, 12, and 24 h. On day 10, oral ciprofloxacin, 500 mg, b.i.d. was initiated. On day 14, blood samples were collected as previously described. Pharmacokinetic analysis was performed to determine if there were differences between the area under the concentration time curve (AUC), maximum serum concentration, Cmax, and time of maximum serum concentration, Tmax, of phenytoin before and during co-administration of ciprofloxacin. Four subjects completed the study. Results of the analysis showed no significant differences between AUC, Cmax, and Tmax of phenytoin before and during ciprofloxacin administration. However, one subject showed marked reductions in both AUC and Cmax. Similar reductions in plasma concentrations have also been reported, resulting in breakthrough seizures. In conclusion, ciprofloxacin was not shown to increase phenytoin plasma concentrations or AUC in healthy volunteers. The potential for decreasing plasma phenytoin concentrations may exist and warrants close monitoring of levels when these two agents are given simultaneously.

Measurement of free phenytoin in blood with a self-contained fiber-optic immunosensor.

We describe the measurement of the anticonvulsant drug phenytoin (5,5-diphenylhydantoin) in human blood and plasma using a self-contained fiber-optic immunosensor which gave a reversible response to changes in concentration. No regenerative treatment of the immunosensor was required between measurements. The analytical signal depended on the degree of energy transfer from B-phycoerythrin labeled with phenytoin to Texas Red labeled anti-phenytoin antibody. Dextran 70K was added to the reagent system to equalize the oncotic pressure across the encapsulation membrane. A gas chromatography reference method was used to measure free drug concentrations. Regression analysis for plasma samples gave the relationship (sensor) = 1.02 (reference) + 0.07 microM; Syx = 1.00 microM; r = 0.953; sensor mean 4.45 microM; reference mean 4.31 microM. Sensor performance in plasma and whole blood was essentially equivalent. We demonstrate the feasibility of measuring free phenytoin directly in blood and suggest that the sensor design is generally applicable for the measurement of other haptens in blood.