Receiving Phenytoin Monotherapy Research Articles

Influenza immunization does not predominantly alter levels of phenytoin, and cytochrome P-450 enzymes in epileptic patients receiving phenytoin monotherapy

ObjectiveThe study aims to test the effect of influenza vaccination on phenytoin, CYP2C9, and IFNγ levels in epileptic patients receiving phenytoin monotherapy MethodsThirty-one epileptic patients receiving stable-dose phenytoin monotherapy were enrolled onto the study. Serum concentrations of phenytoin, CYP2C9, and IFNγ were compared before and after influenza immunization. The participants were given 0.5 mL of quadrivalent influenza vaccine types A and B subvirion. Blood samples were drawn at baseline, and days 3, 7, 14 post-immunization. The outcomes were levels of phenytoin, CYP2C9, IFNγ, and the incidence of adverse events. ResultsNo significant changes in serum phenytoin, IFNγ, and CYP2C9 levels between baseline and days 3, 7, and 14 after immunization were found. The mean levels of phenytoin, IFNγ, and CYP2C9, respectively, were 11.94 ± 7.43, 1.14 ± 0.98, and 47.69 ± 37.53 pg/mL (baseline); 12.15 ± 6.57, 2.13 ± 3.41, and 49.44 ± 39.83 pg/mL (day 3); 12.19 ± 7.69, 1.15 ± 0.94, and 49.48 ± 33.83 pg/mL (day 7); 12.79 ± 7.94, 2.15 ± 3.11, and 53.65 ± 40.91 pg/mL (day 14). The incidence of vaccine-related adverse events, which were generally mild and resolved without clinical consequences, was 58.1 %. No seizure or changes in seizure frequency were observed during the study. One patient experienced dizziness and ataxia which were symptoms attributed to phenytoin toxicity (34.57 μg/mL) by day 14. ConclusionsInfluenza vaccine has no significant effect on the serum phenytoin and CYP2C9 levels in epileptic patients receiving chronic phenytoin monotherapy. The administration of influenza vaccine to epileptic patients receiving phenytoin monotherapy appears to be safe. Therefore, it is not necessary to routinely measure the serum phenytoin level after influenza immunization.

A common polymorphism in the SCN1A gene associates with phenytoin serum levels at maintenance dose

A broad range of phenytoin doses is used in clinical practice, with the final 'maintenance' dose normally determined by trial and error. A common functional polymorphism in the SCN1A gene (one of the genes encoding the drug target) has been previously associated with maximum dose of phenytoin used clinically, and also maximum dose of carbamazepine, another antiepileptic drug with the same drug target. We have related variation at the SCN1A IVS5-91 G>A polymorphism to maximum dose and to maintenance dose of phenytoin in 168 patients with epilepsy treated with phenytoin. We also related genotype to phenytoin serum levels at maximum dose and at maintenance dose of phenytoin. We genotyped the polymorphism using an Applied Biosystems Taqman assay. The polymorphism is associated with phenytoin serum concentration at maintenance dose (P=0.03). In a reduced cohort of 71 patients receiving phenytoin monotherapy this association is also significant (P=0.03). Neither association remains significant after Bonferroni correction for multiple testing. These results are not a replication of the original study. They do, however, support the hypothesis that this polymorphism influences the clinical use of phenytoin. They also demonstrate the utility of using multiple phenotypes in pharmacogenetics studies, particularly when attempting to separate pharmacokinetic and pharmacodynamic effects. As the SCN1A polymorphism affects phenytoin pharmacodynamics, it is particularly useful to obtain data on serum levels in addition to dose because association of a pharmacodynamic variant may be stronger with serum levels than dose as the serum level may eliminate or reduce pharmacokinetic variability.

Clinical evaluation of plasma free phenytoin measurement and factors influencing its protein binding

The relationship between free phenytoin concentrations and clinical responses, and the factors influencing protein binding of phenytoin were investigated. A total of 119 plasma samples from 70 patients treated orally with phenytoin were analysed. The mean free phenytoin concentration was significantly higher in the patients who received phenytoin monotherapy and were classified as having a complete response (1.25 +/- 1.09 microg/ml) than that in the partial response group (0.59 +/- 0.07 microg/ml), whereas the mean total concentrations were not significantly different between the two groups. Samples were divided into three groups based on the free fraction of phenytoin, i.e. low, <5%; medium, 5%-10%; high, > 10%. The mean age (55.3 +/- 10.9 years) was significantly higher in the high group than in the low (42.7 +/- 21.2 years) and medium (42.8 +/- 16.0 years) groups. The mean creatinine clearance (CLcr) (55.3 +/- 10.9 ml/min) and serum albumin concentration (3.30 +/- 1.25 g/dl) were significantly lower in the high group than the low (88.3 +/- 29.0 ml/min and 4.08 +/- 0.50 g/dl, respectively) and medium (95.0 +/- 32.8 ml/min and 3.95 +/- 0.92 g/dl, respectively) groups. These results suggest that the free phenytoin concentration, rather than the total concentration, is more useful for monitoring antiepileptic effects in patients receiving phenytoin monotherapy. It was also found that the free phenytoin fraction was significantly influenced by aging, CLcr and serum albumin levels.

In Vivo Binding Characteristics of Phenytoin to Serum Proteins in Monotherapy for Adults With Epilepsy

The aim of the present study was to determine the binding characteristics of phenytoin (PHT) to serum proteins in the adults. Binding parameters of PHT to serum proteins in our study were compared with in vivo or in vitro binding parameters of PHT to serum proteins reported by other investigators. Serum samples in the study were obtained from 36 adult patients (17 men, 19 women) receiving PHT monotherapy. A total of 43 steady-state concentrations were analyzed in the study. Patients' age ranged from 16 to 73 years (mean [SD], 42.9 [14.7] years). The in vivo population binding parameters of PHT to serum proteins and theoretical minimal unbound serum PHT fraction (fu) were determined using an equation derived from the Scatchard equation. The association constant (K) was 0.014 L x micromol(-1), whereas the total concentration of binding sites (n(Pt)) was 754 micromol x L(-1). The number of binding sites per albumin molecule (n) was 1.16, whereas binding ability (n.K) was 0.016 L x micromol(-1). The fu was 0.087. The n.K is approximately 1.2 times higher in PHT monotherapy patients of Pospísil and Perlík (ie, 0.0191 L x micromol(-1)) than in all our patients. The association constant is approximately 1.3 times higher in the in vitro study of Monks et al (ie, 0.0186 L x micromol(-1)) than in our study, whereas n is similar between the two studies. The fu in our patients is similar to the unbound serum PHT fraction in patients receiving PHT therapy reported by Richens (ie, 0.1). Our results suggest that there may be small differences in the binding affinity of PHT to serum proteins between in vivo and in vitro studies. The unbound serum fraction of PHT in epileptic patients can be assumed to be relatively constant in the therapeutic concentration range of PHT.

Ticlopidine inhibits phenytoin clearance.

Because cases of phenytoin toxicity during concomitant ticlopidine therapy have been reported, we investigated the effects of multiple doses of ticlopidine on phenytoin pharmacokinetics in six patients receiving phenytoin monotherapy. Two steady-state dosing rate and serum phenytoin minimum concentration (Cmin) pairs were obtained for each patient administered oral phenytoin alone, then phenytoin plus 250 mg ticlopidine twice daily. All patients had serum Cmin ticlopidine values of 0.06 to 0.25 microg/mL when receiving ticlopidine. Individual pharmacokinetic parameters for phenytoin were calculated. The Michaelis-Menten constant (Km) was determined as the slope and maximum velocity (Vmax; equivalent to the maximal rate of elimination or the maximum daily dose that can be metabolized) as the y-intercept of the linear Michaelis-Menten plot. Mean phenytoin Km significantly increased from 5.8 to 12.3 during ticlopidine coadministration compared with administration of phenytoin alone (P = .02). Mean phenytoin Vmax was not significantly changed by the coadministration of ticlopidine. These data indicate that ticlopidine inhibits the clearance and alters the clinical pharmacokinetics of phenytoin so that dosage adjustment of phenytoin should be considered when ticlopidine is coadministered. The results are consistent with previous human liver microsome findings that ticlopidine is a potent inhibitor of CYP2C19, a P450 isozyme that is significantly responsible for phenytoin metabolism.

Differential kinetics of phenytoin in elderly patients.

The elderly have a relatively high risk of developing adverse drug reactions. Phenytoin continues to be a preferred drug for treating generalised tonic-clonic seizures in the elderly and simple partial seizures that generalise. Phenytoin is eliminated almost entirely by hepatic oxidation. The principle enzymes responsible are cytochrome P450 (CYP)2C9 and CYP2C19. CYP2C9 is saturated by therapeutic doses of phenytoin, and at steady state both enzymes are probably operant in most people. The nonlinear pharmacokinetics of phenytoin make it a difficult drug for which to establish safe and effective administration regimens. An important area of inquiry is whether the differential disposition kinetics of phenytoin in the elderly render its administration an even more difficult challenge. Moreover, since the elderly are generally subject to more polypharmacy than younger adults, are they, as a result, subject to either more frequent or more severe drug interactions with phenytoin than younger adults? In order to examine these issues we were interested in learning the extent to which old age might affect the plasma protein binding of phenytoin, its hepatic metabolism and, ultimately, its pharmacokinetic profile. With regard to the latter we looked carefully at the methods that have been used to characterise the disposition kinetics of phenytoin in general, and in the elderly, in particular. There are many conflicting findings with regard to the effect of age on the disposition kinetics of phenytoin. However, the strategies used for estimating kinetic parameters for phenytoin [viz the maximum rate of metabolism/elimination (Vmax) and the Michaelis-Menton constant (Km)] exhibit deficiencies that could account for some of the disparate findings. Certainly, more careful prospective studies focusing on the effects of age on phenytoin disposition kinetics are warranted. However, in light of the information currently available, no special attention need be paid to the initiation of phenytoin administration in elderly patients who are taking multiple anticonvulsants. On the other hand, for the elderly receiving phenytoin monotherapy, the initiation of phenytoin administration should occur at lower doses than would be customary for younger adults, and phenytoin blood concentrations should be appropriately monitored in order to evaluate individual Vmax and Km values for informed dosage adjustments.

Folate Deficiency, Anticonvulsant Drugs, and Psychiatric Morbidity

The folic acid (FOA) level was determined in serum and erythrocytes in 100 epileptic patients and 100 control patients using a luminescence assay. A lowered FOA concentration in serum, erythrocytes, or both was observed in 15% of the epileptic patients and in 2% of the control group. In the epileptic patients, the FOA in the serum and in the erythrocytes was significantly lower than that in the control group. Patients receiving carbamazepine monotherapy had a significantly lower FOA level in the erythrocytes than did patients receiving phenytoin monotherapy. The FOA level showed a negative correlation to the duration of epilepsy. None of the patients with lowered FOA had a normal mental status. The course of the supplementation treatment with 5 mg folinic acid (or FOA) of four patients with FOA deficiency could be monitored psychopathometrically. All four patients showed an improvement in their well-being and the majority of measured variables of the cognitive performance.

New Pharmacokinetic Methods II: Determination of the Presence or Absence of Product Inhibition in Drugs with Nonlinear Pharmacokinetics

We show that for drugs metabolized by one enzyme the slope of a plot of serum concentration (C) versus 1/clearance (CL) is linear with a value of 1/Vmax in the presence of substrate saturation and may be linear (rarely) or curved (usually) with a slope always greater than 1/Vmax in the presence of substrate saturation and product inhibition (competitive, noncompetitive, or uncompetitive) when the serum concentration of product varies with the serum concentration of substrate. Serum concentration, CL, and Vmax were determined for a group of six subjects receiving phenytoin monotherapy using three approaches. With each approach: 1) a plot C versus 1/CL was linear (r greater than or equal to 0.738, P less than .01); 2) the slope of this regression line did not differ significantly (P greater than .30) from 1/Vmax. We conclude: 1) our method is a simple and useful method for determination of mechanism of a drug's nonlinear pharmacokinetics (substrate saturation versus substrate saturation and product inhibition), 2) phenytoin has nonlinear pharmacokinetics due to substrate saturation only in man.

New Pharmacokinetic Methods: L Estimation of Mean Serum Concentration From Trough Serum Concentration

An equation is derived to estimate mean steady state serum concentration (Css) from trough steady state serum concentration (Cmin) which can be used for drugs with either linear or nonlinear pharmacokinetic properties. In 15 subjects receiving phenytoin monotherapy, estimated Css did not differ significantly from measured Css, while Cmin differed significantly (P less than .0001) from measured Css and estimated Css. Clearance (CL) and elimination half-life (t1/2) values determined by stable isotope tracer methods or by standard equations and measured Css or estimated Css did not differ significantly, while CL and t1/2 values calculated with standard equations and Cmin differed significantly (P less than .02) from values obtained by any of the other three methods. We conclude: 1) Cmin values and CL and t1/2 values calculated with Cmin values may differ significantly from Css values and CL and t1/2 values calculated with Css; 2) accurate estimates of Css and of CL and t1/2 can be obtained using our procedure to correct a Cmin value to an estimated Css value.

Prenatal Prediction of Risk of the Fetal Hydantoin Syndrome

The well-known teratogenicity of several anticonvulsant medications is associated with an elevated level of oxidative metabolites that are normally eliminated by the enzyme epoxide hydrolase. In this study, we attempted to determine whether infants who are at risk for congenital malformations could be identified prenatally by the measurement of epoxide hydrolase activity. Before fetuses at risk could be identified, it was necessary to measure epoxide hydrolase activity in a randomly selected sample of amniocytes from 100 pregnant women. According to a thin-layer chromatographic assay, the randomly selected sample population had an apparently trimodal distribution, suggestive of an enzyme regulated by a single gene with two allelic forms. Fetuses homozygous for the recessive allele would have low epoxide hydrolase activity and would therefore be at risk if exposed to anticonvulsant drugs during gestation. In a prospective study of 19 pregnancies monitored by amniocentesis, an adverse outcome was predicted for four fetuses on the basis of low enzyme activity (less than 30 percent of the standard). In all four cases, the mother was receiving phenytoin monotherapy, and after birth the infants had clinical findings compatible with the fetal hydantoin syndrome. The 15 fetuses with enzyme activity above 30 percent of the standard were not considered to be at risk, and all 15 neonates lacked any characteristic features of the fetal hydantoin syndrome. These preliminary results suggest that this enzymatic biomarker may prove useful in determining which infants are at increased risk for congenital malformations induced by anticonvulsant drugs.