Metabolic interactions of phenytoin in the rat: effect of coadministration with the anticonvulsant drugs sodium valproate, sulthiame, ethosuximide or phenobarbital

Rats were administered with 50 mg/kg phenytoin (PHT), twice a day, for five consecutive days and with a second anticonvulsant drug in addition for a further five days. Analysis of 24 hr urine samples for content of unmetabolized PHT and its major metabolite 5-(p-hydroxyphenyl)-5-phenylhydantoin (pHPPH) indicates that PHT hydroxylation was significantly inhibited by sulthiame coadministration since during the test period (days 6-10) the concentrations of PHT and pHPPH in urine were significantly increased and decreased respectively. In contrast, sodium valproate, ethosuximide and phenobarbital had no significant effect on the urinary excretion pattern of PHT. These data correlate with changes in plasma and brain PHT concentrations.     

Modelling of the pharmacodynamic interaction between phenytoin and sodium valproate

1. Treatment of epilepsy with a combination of antiepileptic drugs remains the therapeutic choice when monotherapy fails. In this study, we apply pharmacokinetic-pharmacodynamic modelling to characterize the interaction between phenytoin (PHT) and sodium valproate (VPA).
2. Male Wistar rats received a 40 mg kg⁻¹ intravenous dose of PHT over 5 min either alone or in combination with an infusion of VPA resulting in a steady-state concentration of 115.5±4.9 μg ml⁻¹. A control group received only the infusion of VPA. The increase in the threshold for generalized seizure activity (ΔTGS) was used as measure of the anticonvulsant effect.
3. PHT pharmacokinetics was described by a pharmacokinetic model with Michaelis-Menten elimination. The concentration-time course and plasma protein binding of PHT were not altered by VPA. The pharmacokinetic parameters V_max and K_m were, respectively, 294±63 μg min⁻¹ and 7.8±2.4 μg ml⁻¹ in the absence of VPA and 562±40 μg min⁻¹ and 15.6±0.9 μg ml⁻¹ upon administration in combination with VPA.
4. A delay of the onset of the effect relative to plasma concentrations of PHT was observed. The assessment of PHT concentrations at the effect site was based on the effect-compartment model, yielding mean k_e0 values of 0.128 and 0.107 min⁻¹ in the presence and absence of VPA, respectively.
5. A nonlinear relationship between effect-site concentration and the increase in the TGS was observed. The concentration that causes an increase of 50% in the baseline TGS (EC_50%TGS) was used to compare drug potency. A shift of EC_50%TGS from 13.27±3.55 to 4.32±0.52 μg ml⁻¹ was observed upon combination with VPA (P<0.01).
6. It is concluded that there is a synergistic pharmacodynamic interaction between PHT and VPA in vivo.

     

Certain aspects of interaction between sodium valproate and other anticonvulsant drugs in the therapy of epilepsy in children.

The serum valproate (VPA) concentration and the clinical effects of polytherapy with other antiepileptic drugs: phenobarbital (PB), clonazepam (CZP), diazepam (DZ), clobazam (CLO), ethosuximide (ESX) were estimated. VPA serum levels were reduced when this drug was combined with phenobarbital. Clobazam given together with valproate led to an increase in the serum concentration of the former drug. VPA serum levels were without significant changes when the drug was combined with either ethosuximide or 1-4-benzodiazepines. The best therapeutical effects were found after polytherapy sodium valproate with ethosuximide and clobazam in primary generalized seizures.     

Pharmacodynamic interaction between phenytoin and sodium valproate changes seizure thresholds and pattern

1. In this study we used cortical stimulation to assess the effects of phenytoin (PHT), sodium valproate (VPA), and their interaction on total motor seizure and on the constituent elements of the seizure.
2. PHT (40 mg kg⁻¹) was administered as an intravenous bolus infusion to animals receiving either a continuous infusion of VPA or saline. VPA plasma concentration was maintained at levels that produced no detectable anticonvulsant effect.
3. Analysis of ictal components (eyes closure, jerk, gasp, forelimb, clonus, and hindlimb tonus) and their durations revealed both qualitative and quantitative differences in drug effects.
4. The anticonvulsant effect is represented by the increase in the duration of the stimulation required to reach a given seizure threshold. PHT significantly increased the duration of the stimulation and of the motor seizure. This increase was greatly enhanced by VPA. In addition, ictal component analysis revealed that the combination of PHT and VPA causes the reduction of a specific seizure component (JERK).
5. Neither the free fraction of PHT nor the biophase equilibration kinetics changes in the presence of VPA. It is concluded that the synergism may be due to a pharmacodynamic rather than a pharmacokinetic interaction.

     

丙戊酸钠与苯妥英钠或卡马西平相互作用的血浓度观察

本文报告丙戊酸钠和苯妥英钠或卡马西平合用治疗各型癫痫９０例，丙戊酸钠使苯妥英钠和卡马西平血浓度下降；苯妥英钠和卡马西平是强有力的肝酶诱导剂，使丙戊酸钠血浓度降低，作者认为，抗癫痫药之间的相互作用错综复杂，临床上最好选择单一用药，昼避免联合用药。     

高效液相色谱-质谱联用法同时测定苯巴比妥、丙戊酸钠、苯妥英钠和卡马西平的血药浓度

目的 建立高效液相色谱-质谱联用法以便同时测定人血浆中苯巴比妥、丙戊酸钠、苯妥英钠和卡马西平(均为抗癫痫药物)的血药浓度.方法 以霉酚酸为内标,血浆样品经乙睛直接沉淀蛋白后,采用Zorbax Eclipse XDB-C18 色谱柱(2.1 mm×150.0mm,3.5 μpm)进行分离,以0.05%乙酸铵-甲醇(47.53)为流动相,流量0.2 mL·min-1,柱温30℃;通过电喷雾离子源(ESI ),正负离子同时检测.结果 苯巴比妥、丙戊酸钠、苯妥英钠和卡马西平线性范围分别为0.5～80.0,2.5～200.0,0.5～40.0和0.2～24.0 μg·ML-1;最低检测限分别为0.05,0.20,0.10和0.01μg·mL-1;γ均大于0.99.高、中、低3个浓度的日内精密度小于3%,日间精密度小于15%,绝对回收率均大于70%.结论 本方法简便、快速、灵敏、重现性好,能够有效地检测人血浆中4种药物的含量.     

Effect of p-isopropoxyphenylsuccinimide monohydrate on the anticonvulsant action of carbamazepine,phenobarbital, phenytoin and valproate in the mouse maximal electroshock-induced seizure model

This study was designed to determine the effects of p-isopropoxyphenylsuccinimide monohydrate (IPPS) on the protective action of four classical antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) in the mouse maximal electroshock seizure model.Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2 s stimulus duration) delivered via auricular electrodes. Acute adverse-effect profiles with respect to motor performance, long-term memory and skeletal muscular strength were measured along with total brain antiepileptic drug concentrations. Results indicate that IPPS administered intraperitoneally (ip) at doses of 75 and 150 mg/kg significantly elevated the threshold for electroconvulsions in mice. IPPS at lower doses of 18.75 and 37.5 mg/kg had no impact on the threshold for electroconvulsions in mice. Moreover, 37.5 mg/kg IPPS significantly enhanced the anticonvulsant activity of phenytoin and valproate, but not that of carbamazepine or phenobarbital, in the maximal electroshock seizure test in mice. IPPS (18.75 mg/kg) had no impact on the antiseizure action of phenytoin and valproate against maximal electroshock-induced seizures in mice. Pharmacokinetic experiments revealed that IPPS did not alter total brain concentrations of phenytoin or valproate in mice.In conclusion, the enhanced anticonvulsant action of phenytoin and valproate by IPPS in the mouse maximal electroshock-induced seizure model and lack of pharmacokinetic interactions make the combinations of IPPS with phenytoin and valproate of pivotal importance for further experimental and clinical studies. The combinations of IPPS with carbamazepine and phenobarbital are neutral from a preclinical viewpoint.     

A double-blind, placebo-controlled interaction study between oxcarbazepine and carbamazepine, sodium valproate and phenytoin in epileptic patients.

1. The effect of carbamazepine (CBZ), sodium valproate (VPA) and phenytoin (PHT) on the pharmacokinetics of oxcarbazepine (OXC) was explored in three groups of 12 epileptic patients taking one of these drug as monotherapy. 2. Each patient took a single 600 mg dose of OXC followed 7 days later by 3 weeks' treatment with OXC 300 mg thrice daily and matched placebo in random order. 3. Seven untreated patients, acting as controls, were prescribed the single OXC dose and 3 weeks' active treatment only. 4. In those patients completing the study, the area under the concentration-time curve (AUC) at steady-state for hydroxycarbazepine (OHCZ), the active metabolite of OXC, was significantly lower in the CBZ-treated group than in controls (P < 0.05). 5. No other differences in AUCs or elimination half-lives for OHCZ were found between treated and untreated patients following single or multiple OXC dosing. 6. Median AUCs of CBZ, VPA and PHT during a dosage interval did not differ significantly after treatment with OXC and placebo. 7. Ten patients completing the study complained of side-effects during treatment with OXC compared with one taking placebo (P < 0.01). 8. There were no important changes in cognitive function testing during administration of OXC compared with placebo. 9. Standard doses of OXC can be given as add-on therapy in epileptic patients receiving CBZ, VPA or PHT without producing a clinically relevant pharmacokinetic interaction.     

Etifoxine: evaluation of its anticonvulsant profile in mice in comparison with sodium valproate, phenytoin and clobazam

The anticonvulsant potential of 6-chloro-2-(ethylamino)-4-methyl-4-phenyl-4H-3,1-benzoxazine (etifoxine), a non-benzodiazepine tranquilizer, was evaluated in mice in comparison to valproate, phenytoin and clobazam. Maximal seizures were induced by electroshock (MES) and the chemical convulsants pentetrazol (PTZ), picrotoxin (PTX), bicuculline (BIC), isoniazid (INH), nicotine (NIC) and strychnine (STR). Tonic extensor convulsions were prevented by etifoxine in the following rank order of potency (ED50 values with seizure tests): 39.5 (PTX), 101 (PTZ), 101 (MES), 154 (INH), 181 (NIC), 397 (BIC), and greater than 800 mg/kg p.o. (STR). Clonic seizures were induced by threshold doses of PTZ, PTX and pilocarpine (PIL) and antagonized by etifoxine at ED50 values of 181 (PIL), 221 (PTZ), and greater than 800 mg/kg p.o. (PTX). Hence, etifoxine blocked both tonic and clonic seizures but was more potent against the tonic component. The anticonvulsant profile of etifoxine appeared similar to that of valproate. However, in terms of potency, protective indices (ED50 rotarod/ED50 seizure test) and therapeutic indices (LD50/ED50 seizure test) etifoxine was on an average 3.7, 12 and 14 times superior to valproate, respectively. It is concluded that etifoxine has a marked anticonvulsive potential and may be beneficially used in epileptic disorders, especially of the grand mal type.     

Lack of pharmacokinetic interaction between nifedipine, sparteine and phenytoin in man.

Nifedipine, sparteine and phenytoin were administered orally to eight healthy subjects separately and as a 'cocktail' on four different occasions to investigate any kinetic interactions. All subjects were extensive metabolizers of sparteine. After drug intake plasma and urine samples were collected up to 32 h and the concentrations of parent drugs and main metabolites were measured. Clearances and formation clearances were not significantly different after single substrate and 'cocktail' administration. Low or non significant correlation coefficients were found between the oxidation of the individual substrates or formation of their metabolites. With this strategy of simultaneous administration of substrates ('cocktail') it appears possible to characterize (and correlate) activities of different cytochrome P-450 isoenzymes, without the disturbing influence of intraindividual variation of drug oxidation with time.     

Lack of pharmacokinetic interaction between lansoprazole and intravenously administered phenytoin

The objective of this randomized, double-blind, two-period crossover study was to investigate whether concomitant steady-state lansoprazole influences the pharmacokinetics of CYP2C9 substrates using single intravenously dosed phenytoin as a model substrate. In addition, the safety of concomitant administration of these two drugs was evaluated. Twelve healthy, nonsmoking, adult male subjects received 60 mg lansoprazole or placebo once daily for 9 days during each study period. On the morning of day 7, each subject received a single 250 mg intravenous phenytoin dose. There were no statistically significant differences between the two regimens for mean phenytoin Cmax or tmax. There was a minor (< 3%) but statistically significant difference between the two regimens for phenytoin AUC resulting from a very low intrasubject coefficient of variation (2.3%). The treatment and control mean plasma concentration phenytoin profiles were virtually super-imposable. In conclusion, concomitant multidose lansoprazole administration is unlikely to have any clinically significant effect on the pharmacokinetics of CYP2C9 substrates in general or intravenous phenytoin specifically.     

Teratogenic acitivity of the antiepileptic drugs phenobarbital,phenytoin, and primidone in mice

The teratogenic activity of phenobarbital, phenytoin, and primidone was studied in mice derived from the ICI pathogen free strain. The drugs were administered in the diet or by gastric intubation either from days 6–16 or 12–16 of pregnancy (day of vaginal plug is day 1). This covered the period during which the mice are susceptible to agents inducing cleft palate. The mothers were killed 1 day before term and the fetuses were examined. Cleft palates were rarely seen in the controls, the incidence being only 3 out of 1103 (0.3%) fetuses. The incidence of cleft palate in mice treated with phenobarbital 50 or 150 mg/kg in the diet was 0.6 and 3.9%, with phenytoin 40 and 120 mg/kg by intubation, or 250 mg/kg in the diet was 0, 11.1 and 10.2%, and with primidone 100 to 250 mg/kg by intubation or 500–2500 mg/kg in the diet ranged up to 15%. Since changes in blood folate concentrations following the use of anticonvulsants might be related to the teratogenic effects observed, an attempt was made to antagonize the effects by the simultaneous administration of folinic acid. Folinic acid had no teratogenic action of its own, and had no effect on the incidence of cleft palate induced by phenobarbital in the diet, or by phenytoin by gastric intubation. However, it did significantly potentiate the teratogenic effects of phenytoin administered in the diet (p < 0.002) but significantly reduced the teratogenic effect of primidone given in the diet (p < 0.034).     

苯妥英钠对丙戊酸钠药动学的影响

目的：研究苯妥英钠（PHT）对丙戊酸钠（VLA）在癫痫治疗中的药动学影响及VAL在唾液中与血液中浓度的相关性。方法：监测病人血清中PHT和VAL浓度,用药动学软件PKBP－N1拟合。结果：与VAL单用相比,PHT可显著降低VAL的血中药物浓度,AUC（P＜0．05）,缩短t1/2。VAL的唾液浓度与其血中浓度相关性不显著（P＞0．05）。结论：在癫痫联合用药治疗中,PHT对VAL的药动学有显著影响,故需监测二者的血药浓度,以达到合理用药。此外,不能用唾液中VAL的浓度作为药物浓度指标。     

Adenosinergic mechanisms in anticonvulsant action of diazepam and sodium valproate

The effects of adenosine receptor agonists and antagonists were studied in pentylenetetrazole (PTZ)-induced seizures in rats. Animals were pretreated with the non-specific adenosine receptor antagonist, theophylline (50 and 100 mg/kg, i.p.), or the specific A₁ adenosine receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), in a dose of 1 mg/kg, i.p., followed by 100% anticonvulsant doses of diazepam (4 mg/kg)/sodium valproate (300 mg/kg, i.p.). Subsequently, they were challenged with convulsant doses of PTZ i.e. 60 mg/kg, i.p. It was seen that while DPCPX could not reverse the protection of both the antiepileptic drugs, theophylline significantly reversed this protection, as assessed by percent incidence of seizures and change in latency parameters. In another set of experiments, the rats were pretreated with a combination of subanticonvulsant doses of adenosine (500 mg/kg) or specific adenosine A₁ receptor agonist, cyclopentyladenosine (CPA) and diazepam (0.5 and 1 mg/kg)/sodium valproate (150 mg/kg), prior to PTZ challenge. We observed a decrease in incidence and increase in latency of seizures following either combination. The protection observed was independent of the hypothermic and hypotensive effects of adenosine and CPA. These results indicate that though A₁ agonist enhances the protection of diazepam and sodium valproate, a direct involvement of adenosine A₁ receptor in anticonvulsant action of these drugs is doubtful.     

Phenytoin induced chorea in a pediatric patient: An interaction between phenytoin, phenobarbital and clobazam

A 3-year-old female patient developed chorea possibly due to an interaction between phenytoin, phenobarbital and clobazam used for generalized tonic clonic seizures. Phenytoin withdrawal resulted in recovery within 24 hours. Post reaction computerized tomography (CT)-scan of brain was normal. Combined use of anti-seizure drugs and interactions between them may be responsible for the reaction. Therapeutic drug monitoring is important while prescribing two or more anti-seizure drugs.     

Interaction between valproate formulation and phenytoin concentrations

Changes in phenytoin concentrations caused by switching valproate formulations with different absorption rates were retrospectively investigated in eleven epileptic patients receiving treatment with both drugs. Total plasma phenytoin concentrations were measured before and after a standard tablet of valproate was replaced by the same dose as a slow-release tablet.The mean plasma phenytoin level rose significantly from 14.4 to 18.7 g·ml^–1. Nine of eleven patients had markedly increased phenytoin levels (by 21 to 72%), and two developed toxic symptoms.The results indicate that changing valproate formulations can cause major alterations in the plasma concentration of co-administered phenytoin.     

The development of tolerance to the anticonvulsant effects of clonazepam, but not sodium valproate, in the amygdaloid kindled rat

The effects of chronic treatment with clonazepam and sodium valproate were studied on kindled amygdaloid seizures in rats. Fully kindled rats were given an intraperitoneal (i.p.) injection of either vehicle (1.0 ml/kg), clonazepam (0.3 mg/kg) or sodium valproate (200 mg/kg) twice daily for 12 days. Each rat was stimulated through an amygdaloid electrode 30 min after the morning dose. While both drugs initially blocked and kindled seizure (P less than 0.01), the results showed a significant trend (P less than 0.02) in the development of tolerance to the anticonvulsant action of clonazepam but no significant tolerance to the action of valproate.