Plasma Phenytoin Concentrations Research Articles

Phenotypic evaluation of CYP2C9 by way of phenytoin metabolic ratio (PMR)

Aims Validation of PMR as a phenotypic marker of CYP2C9 in the Jewish Israeli population. Methods Seventy-nine Jewish Israeli subjects collected urine over 24 hours following a single dose of 300 mg phenytoin (PHT). A single blood sample was drawn after 12 hours. PMR, a putative index of CYP2C9 activity, was derived from the ratio of urinary 5-(4-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) to mid-interval plasma PHT concentration. CYP2C9 genotype was identified by PCR followed by incubation with restriction enzymes. Results The ethnic composition of the study population was reflective of the Jewish groups residing in Israel. PMR values exhibited 18-fold inter-individual variability with a typical Gaussian frequency distribution, which was skewed to the right. Forty-one subjects were homozygous for the wild-type allele (CYP2C9*1), 32 were carriers of one mutated allele (16 CYP2C9*2 and 16 CYP2C9*3), and 6 were carriers of 2 mutated alleles. PMR exhibits gene-dose effect so that among CYP2C9*1 homozygous, PMR was 16.17±9.76 ml/min (95% CI, 13.10 to 19.26) and significantly greater than in CYP2C9*2 heterozygous (8.54±4.33 ml/min, 95% CI, 6.24 to 10.85, p<0.05) and CYP2C9*3 heterozygous (7.33±3.55 ml/min, 95% CI, 5.44 to 9.22, p<0.001) or carriers of 2 variant alleles (6.73±4.22 ml/min, 95% CI, 2.30 to 11.15, p<0.01). Conclusions PMR exhibits marked inter-individual variability and it correlates with CYP2C9 genotype. Its use as a reliable marker of CYP2C9 activity in-vivo should be further evaluated. Clinical Pharmacology & Therapeutics (2005) 77, P60–P60; doi: 10.1016/j.clpt.2004.12.121

Evaluation of Phenytoin Dosage Regimens Based on Genotyping of CYP2C Subfamily in Routinely Treated Japanese Patients

Two research groups have reported the effect of genetic polymorphisms of CYP2C9 and CYP2C19 on the pharmacokinetic parameters of phenytoin in Japanese epileptic patients. We measured the plasma phenytoin concentrations at steady-state in 20 routinely treated Japanese patients, and evaluated the usefulness of genotyping the CYP2C subfamily in predicting plasma concentrations and determining the dosage regimens of phenytoin. The plasma phenytoin concentrations predicted by genotypes of the CYP2C subfamily were well correlated with the observed concentrations in some patients, but not in some patients. The pharmacokinetic parameters (Vmax and Km) in individual patients, which were obtained from population estimates according to Bayes' theorem, showed considerable interindividual variability even among patients with the same genotype. In addition, we assessed the effect of plasma protein binding on the residual interindividual variability in the clearance of phenytoin; however, there was no significant correlation between the unbound fraction and the intrinsic metabolic activity (Vmax/Km). These findings suggested that the mechanism responsible for the large variability in the clearance of phenytoin is not completely resolved, and that we should not overestimate the usefulness of genotyping the CYP2C subfamily in determining the dosage regimens of the drug.

Phenytoin treatment reduces atherosclerosis in mice through mechanisms independent of plasma HDL-cholesterol concentration

Phenytoin (PHT) increases high density lipoprotein cholesterol (HDL-C) and reduces coronary artery disease mortality in humans. We report the results of PHT treatment on atherosclerosis susceptibility and lipid profile in four different types of mouse: control C57BL/6 mice and cholesteryl ester transfer protein transgenic mice as models of fatty streak, and LDL receptor-deficient mice and apolipoprotein E-deficient mice as models of mature atherosclerosis. Each mouse type was fed an appropriate diet to induce atherosclerosis and prevent liver toxicity. PHT treatment demonstrated a protective effect in all models. Reduction in aortic atherosclerotic area by PHT treatment was more evident in early atherosclerosis (2.3-fold) than in mature atherosclerosis (decreases of 40 and 23%, respectively, but only in mice in the upper 50% percentile of plasma PHT concentration). Atherosclerosis prevention was not concomitant with a consistent increase in HDL-C or any other protective change in the lipid profile. Different analyses of potential antiatherogenic HDL functions did not provide additional information. Microarray liver gene expression analyses identified a potential atheroprotective mechanism characterized by decreased expression of syndecan-4, RhoA2, double LIM protein-1, zeta-chain-associated protein kinase-70 and interleukin 6 receptor-α. However, to demonstrate that these changes are part of a PHT-antiatherogenic effect, they will need to be found also in arteries, maintained at protein level and proved to be causal rather than reactive.

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.

Overview of the Clinical Pharmacokinetics of Oxcarbazepine

Oxcarbazepine (GP 47680, 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine- 5-carboxamide) is an antiepileptic drug registered worldwide by Novartis under the trade name Trileptal((R)). Trileptal((R))is approved as adjunctive therapy or monotherapy for the treatment of partial seizures in adults and in children. In the US, Trileptal((R)) is approved as adjunctive therapy in adults and in children >/=4 years of age and as monotherapy in adults and in children.Trileptal((R))is currently marketed as 150, 300 and 600mg film-coated tablets for oral administration. A 60 mg/mL (6%) oral suspension formulation has also been registered worldwide.Oxcarbazepine and its pharmacologically active metabolite, 10-monohydroxy derivative (MHD; 10,11-dihydro-10-hydro-carbamazepine; GP 47779) show potent antiepileptic activity in animal models comparable to that of carbamazepine (Tegretol((R))) and phenytoin. Oxcarbazepine and MHD have been shown to exert antiepileptic activity by blockade of voltage-dependent sodium channels in the brain.Oxcarbazepine is rapidly reduced by cytosolic enzymes in the liver to MHD, which is responsible for the pharmacological effect of the drug. This step is mediated by cytosolic arylketone reductases. MHD is eliminated by conjugation with glucuronic acid. Minor amounts (4% of the dose) are oxidised to the pharmacologically inactive dihydroxy derivative (DHD). The absorption of oxcarbazepine is complete. In plasma after a single oral administration of oxcarbazepine the mean apparent elimination half-life (t((1/2))) of MHD in adults was 8-9h. Food has no effect on the bioavailability of the highest strength of the final market image tablet (600mg). At steady state MHD displays predictable linear pharmacokinetics at doses ranging from 300 to 2400mg. In children with normal renal function, renal clearance of MHD is higher than in adults, with a corresponding reduction in the terminal t((1/2)) of MHD. Consequently, although no special dose recommendation is needed, an increase in the dose of oxcarbazepine may be necessary to achieve similar plasma levels to those in adults. In patients with moderate to severe renal impairment (creatinine clearance <30 mL/min), the elimination t((1/2)) of MHD is prolonged with a corresponding 2-fold increase in area under the concentration-time curve. Therefore, a dose reduction of at least 50% and a prolongation of the titration period is necessary in these patients. Mild-to-moderate hepatic impairment does not affect the pharmacokinetics of MHD. Based on in vitro and in vivo findings and compared with antiepileptic drugs such as carbamazepine, phenytoin and phenobarbital, oxcarbazepine has a low propensity for drug-drug interactions. In vitro, MHD inhibits the cytochrome P450 (CYP) 2C19 (ki [inhibition constant] = 88 micromol/L). At oxcarbazepine doses above 1.2g, a 40% increase in the concentration of phenytoin and a 15% increase in phenobarbital levels were observed. Oxcarbazepine/MHD at high doses may slightly increase phenobarbital and phenytoin plasma concentrations. Therefore, when using high doses of oxcarbazepine an adjustment in the dose of phenytoin may be required. In vitro, MHD is only a weak inducer of uridine diphospate (UDP)-glucuronyltransferase (UDPGT) and therefore is unlikely to have an effect on drugs that are mainly eliminated by conjugation through the UDPGT enzymes (e.g. valproic acid and lamotrigine). Weak interactions between MHD and antiepileptic drugs that are strong inducers of CYP enzymes have been identified. Carbamazepine, phenobarbital and phenytoin have been shown to reduce MHD levels by 30-40% when coadministered with oxcarbazepine, with no decrease in efficacy. Oxcarbazepine decreases the plasma hormone levels (ethinylestradiol and levonorgestrel) of oral contraceptives and may therefore have the potential to cause oral contraception failure.

Chloramphenicol is a potent inhibitor of cytochrome P450 isoforms CYP2C19 and CYP3A4 in human liver microsomes.

The inhibitory effect of chloramphenicol on human cytochrome P450 (CYP) isoforms was evaluated with human liver microsomes and cDNA-expressed CYPs. Chloramphenicol had a potent inhibitory effect on CYP2C19-catalyzed S-mephytoin 4'-hydroxylation and CYP3A4-catalyzed midazolam 1-hydroxylation, with apparent 50% inhibitory concentrations (inhibitory constant [K(i)] values are shown in parentheses) of 32.0 (7.7) and 48.1 (10.6) microM, respectively. Chloramphenicol also weakly inhibited CYP2D6, with an apparent 50% inhibitory concentration (K(i)) of 375.9 (75.8) microM. The mechanism of the drug interaction reported between chloramphenicol and phenytoin, which results in the elevation of plasma phenytoin concentrations, is clinically assumed to result from the inhibition of CYP2C9 by chloramphenicol. However, using human liver microsomes and cDNA-expressed CYPs, we showed this interaction arises from the inhibition of CYP2C19- not CYP2C9-catalyzed phenytoin metabolism. In conclusion, inhibition of CYP2C19 and CYP3A4 is the probable mechanism by which chloramphenicol decreases the clearance of coadministered drugs, which manifests as a drug interaction with chloramphenicol.

Pharmacokinetics and clinical effects of phenytoin and fosphenytoin in children with severe malaria and status epilepticus.

Status epilepticus is common in children with severe falciparum malaria and is associated with poor outcome. Phenytoin is often used to control status epilepticus, but its water-soluble prodrug, fosphenytoin, may be more useful as it is easier to administer. We studied the pharmacokinetics and clinical effects of phenytoin and fosphenytoin sodium in children with severe falciparum malaria and status epilepticus. Children received intravenous (i.v.) phenytoin as a 18 mg kg-1 loading dose infused over 20 min followed by a 2.5 mg x kg(-1) 12 hourly maintenance dose infused over 5 min (n = 11), or i.v. fosphenytoin, administered at a rate of 50 mg x min(-1) phenytoin sodium equivalents (PE; n = 16), or intramuscular (i.m.) fosphenytoin as a 18 mg x kg(-1) loading dose followed by 2.5 mg x kg(-1) 12 hourly of PE (n = 11). Concentrations of phenytoin in plasma and cerebrospinal fluid (CSF), frequency of seizures, cardiovascular effects (respiratory rate, blood pressure, trancutaneous oxygen tension and level of consciousness) and middle cerebral artery (MCA) blood flow velocity were monitored. After all routes of administration, a plasma unbound phenytoin concentration of more than 1 microg x ml(-1) was rapidly (within 5-20 min) attained. Mean (95% confidence interval) steady state free phenytoin concentrations were 2.1 (1.7, 2.4; i.v. phenytoin, n = 6), 1.5 (0.96, 2.1; i.v. fosphenytoin, n = 11) and 1.4 (0.5, 2.4; i.m. fosphenytoin, n = 6), and were not statistically different for the three routes of administration. Median times (range) to peak plasma phenytoin concentrations following the loading dose were 0.08 (0.08-0.17), 0.37 (0.33-0.67) and 0.38 (0.17-2.0) h for i.v. fosphenytoin, i.v. phenytoin and i.m. fosphenytoin, respectively. CSF: plasma phenytoin concentration ratio ranged from 0.12 to 0.53 (median = 0.28, n = 16). Status epilepticus was controlled in only 36% (4/11) following i.v. phenytoin, 44% (7/16), following i.v. fosphenytoin and 64% (7/11) following i.m. fosphenytoin administration, respectively. Cardiovascular parameters and MCA blood flow were not affected by phenytoin administration. Phenytoin and fosphenytoin administration at the currently recommended doses achieve plasma unbound phenytoin concentrations within the therapeutic range with few cardiovascular effects. Administration of fosphenytoin i.v. or i.m. offers a practical and convenient alternative to i.v. phenytoin. However, the inadequate control of status epilepticus despite rapid achievement of therapeutic unbound phenytoin concentrations warrants further investigation.

Effects of Phenytoin on Rocuronium-induced Neuromuscular Blockade Using a Rat Phrenic Nerve-diaphragm Preparation

Background: Chronic anticonvulsant therapy with phenytoin antagonizes the action of nondepolarizing muscle relaxants. Rocuronium is a new non depolarizing muscle relaxant of rapid onset and intermediate duration. This study was designed to investigate the effects of phenytoin on rocuronium-induced neuromuscular blockade using a rat phrenic nerve-diaphragm preparation. Methods: Male Sprague-Dawley rats (200 g, n = 70) were randomly allocated into a control group (C, n = 10), three phenytoin-pretreated groups (PP, n = 30) and three phenytoin-non-pretreated groups (PNP, n = 30). In phenytoin-pretreated groups, phenytoin 50 mg/kg/day was administered intraperitoneally once a day for one day (PP), seven days (PP) or twenty eight days (PP). Animals were anesthetized with 40 mg/kg of thiopental sodium intraperitoneally and the diaphragm with the phrenic nerve were dissected, and the phrenic nerve-diaphragm preparation was suspended in 100 ml of Krebs solution in an organ bath. The bath was aerated with 95% O-5% CO at 32, and the phrenic nerve was stimulated with supramaximal intensity using a stimulator. Twitch responses were measured using a precalibrated force displacement transducer and recorded. The cumulative dose-response relationships of rocuronium and phenytoin were determined. After one hour's stabilization, rocuronium 100g was added to the bath, and when a stable 3 - 5 twitch was obtained, incremental 50llg doses of rocuronium were added to obtain more than 95% neuromuscular twitch inhibition at 0.1 Hz. In the phenytoin-non-pretreated group, phenytoin was administered simultaneously with the initial dose of rocuronium to a phenytoin concentration of lg/ml (PNP1), l0g/ml (PNPlO), or 100g/ml (PNP) in Krebs solution. Data were analyzed by probit and logistic models. In the PP group, the plasma concentration of phenytoin was analyzed by high performance liquid chromatography. Results: The dose-response curve of rocuronium was significantly shifted to the left in the PNP group (P group (P

The absorption of gabapentin following high dose escalation

Gabapentins (GBP) is structurally similar to GABA yet its mode of action remains uncertain. It is water-soluble and GI tract absorption occurs via the l-amino acid transport system in the proximal small bowel. It has been suggested that this transportation is capacity limited, thus decreasing GBP bioavailability at higher doses. GBP is not protein bound, therefore, salivary levels might be expected to be similar to those in serum; also the drug does not induce hepatic enzymes and is excreted unmetabolised by the kidney. Within the dose-range normally prescribed, it is devoid of pharmacokinetic (PK) drug interactions with all other anti-epileptic drugs. This study assesses two things in patients with epilepsy: (a) bioavailability of higher doses of GBP (1200–4800 mg per day), and (b) the influence of high dose GBP on between-dose serum concentrations of co-prescribed anti-epileptic drugs. After stabilising at each dosage, a sequence of serum and saliva samples were collected within the dosage interval; GBP and co-medication concentrations were determined and the results subjected to PK modelling. Meaned results from 10 patients indicate that GBP continues to be absorbed in a reasonably linear manner relative to dose up to 4800 mg per day. The study also shows that GBP is transported into saliva, however, salivary concentrations are only 5–10% of those in plasma. Furthermore, the results indicate that GBP, in higher than recommended doses, did not change plasma concentrations of lamotrigine, carbamazepine, carbamazepine-epoxide, vigabatrin, primidone, phenobarbitone or phenytoin when added to treatment. It is concluded that larger than recommended doses of GBP can be efficiently absorbed by some patients and also that GBP plasma levels do not fluctuate greatly between dosage intervals, therefore, twice daily dosage is a possibility.

Involvement of multiple UDP-glucuronosyltransferase 1A isoforms in glucuronidation of 5-(4'-hydroxyphenyl)-5-phenylhydantoin in human liver microsomes.

In humans, orally administered phenytoin, 5,5-diphenylhydantoin, is mainly excreted as 5-(4'-hydroxyphenyl)-5-phenylhydantoin (4'-HPPH) O-glucuronide. Phenytoin is oxidized to 4'-HPPH by CYP2C9 and to a minor extent by CYP2C19, and then 4'-HPPH is metabolized to 4'-HPPH O-glucuronide by UDP-glucuronosyltransferase (UGT). In the present study, 4'-HPPH O-glucuronidation in human liver microsomes was investigated. The metabolite formed by incubation with human liver microsomes, 4'-HPPH, and UDP-glucuronic acid was identified as 4'-HPPH O-glucuronide by liquid chromatography-tandem mass spectrometry analysis. The 4'-HPPH O-glucuronosyltransferase activity in human liver microsomes was not saturated at concentrations up to 500 microM of 4'-HPPH. Any commercially available recombinant human UGTs (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15) expressed in baculovirus-infected insect cells did not show detectable 4'-HPPH O-glucuronide. The 4'-HPPH O-glucuronidation in pooled human liver microsomes was inhibited by beta-estradiol as a typical substrate for UGT1A1 (IC(50) = 21.1 microM) and imipramine as a typical substrate for UGT1A4 (IC(50) = 57.7 microM). The inhibitory effects of propofol as a specific substrate for UGT1A9 (IC(50) = 167.1 microM) and emodin as a substrate for UGT1A8 and UGT1A10 (IC(50) = 287.6 microM) were not prominent. The interindividual difference in the 4'-HPPH O-glucuronidation in 14 human liver microsomes was 28.5-fold (0.023-0.656 nmol/min/mg of protein). The 4'-HPPH O-glucuronosyltransferase activity in 11 human liver microsomes was significantly (r = 0.609, P < 0.05) correlated with the 4-nitrophenol glucuronosyltransferase activity, which is catalyzed by UGT1A6 and UGT1A9. These results suggest that multiple UGT1As such as UGT1A1, UGT1A4, UGT1A6, and UGT1A9 are involved in 4'-HPPH O-glucuronidation in human liver microsomes, although the percentage contribution of each UGT1A could not be estimated. Large interindividual differences in the glucuronidation of 4'-HPPH might be responsible for the nonlinearity of the phenytoin plasma concentration or adverse reactions in humans.

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.

Hypocalcemia-like Electrocardiographic Changes After Administration of Intravenous Fosphenytoin

Fosphenytoin is a prodrug that is metabolized by phosphatases to yield the antiepileptic drug phenytoin plus inorganic phosphate. Thus, fosphenytoin can theoretically alter the electrocardiogram by 2 mechanisms: the direct effects of phenytoin on cardiac conduction and on phosphate binding of calcium, which could indirectly alter cardiac conduction as a result of hypocalcemia. We report the case of a 23-year-old man, weight 73 kg, with a known but untreated seizure disorder who was given prophylactic fosphenytoin, 1500-mg phenytoin equivalents over 85 minutes by intravenous infusion. The patient was normocalcemic before drug infusion. Fosphenytoin produced electrocardiographic changes (prolongation of the ST segment and the QT interval and merging of the T and P waves) consistent with hypocalcemia, and these changes were associated with new-onset reductions in both total and ionized serum calcium concentrations. Plasma phenytoin concentrations were within the therapeutic range during the electrocardiographic changes, and the patient's blood pressure was stable. We interpret these findings as fosphenytoin-related electrocardiographic changes likely attributable to inorganic phosphate-induced hypocalcemia.

Time course of lamotrigine de-induction: impact of step-wise withdrawal of carbamazepine or phenytoin

Objective: The objective of the present analysis is to examine lamotrigine (LTG) pharmacokinetics both during polytherapy with enzyme inducing antiepileptic drugs and to evaluate the time course of de-induction following the step-wise withdrawal of enzyme inducers. Background: LTG pharmacokinetics can be significantly influenced by concomitant AEDs, and the addition of enzyme inducers can markedly increase LTG clearance, thereby reducing serum concentrations. A clinically relevant question is how will LTG clearance and resulting plasma concentrations be altered during concomitant enzyme inducer withdrawal/conversion process. Design/Method: As part of a previously published, active-control, LTG monotherapy trial, dose and plasma concentration data for LTG, carbamazepine (CBZ) or phenytoin (PHT) were obtained. Following the attainment of a LTG target dose of 500 mg/day, CZB or PHT were withdrawn in weekly 20% decrements. Following inducer withdrawal, LTG was then continued as monotherapy for an additional 12 weeks. Plasma concentrations and daily doses of LTG, CBZ, or PHT were obtained at regularly scheduled study visits during inducer withdrawal and during LTG monotherapy. Pharmacokinetic analysis of the plasma concentration data was done to determine the time-course and effect of inducer plasma concentration on LTG oral clearance (Cl o), where LTG Cl o was estimated as the dose/concentration ratio. Results: Of the 156 patients enrolled in this trial, 76 were assigned to LTG arm, 43 completed the withdrawal to monotherapy phase with 28 successfully completing the study. In a subset analysis of completers, LTG Cl o determined prior to withdrawal of the inducers was significantly greater in patients ( n=28) on LTG+PHT (160% increase) than in those ( n=48) receiving LTG+CBZ (62% increase): 1.77±0.77 vs. 1.06±0.41 ml/min/kg, respectively, p=0.017. The significant reduction in LTG Cl o occurred only when CBZ plasma concentrations reached approximately 2 μg/ml or PHT plasma concentrations reached zero. Conclusions: Mean LTG plasma concentrations will approximately double following the withdrawal PHT; however increases of only 60% may occur following the withdrawal of CBZ. Importantly, these data suggest that LTG concentrations would not be expected to increase until the concomitant inducer is almost completely removed.

Remacemide hydrochloride as an add-on therapy in epilepsy: a randomized, placebo-controlled trial of three dose levels (300, 600 and 1200 mg / day) in a Q.I.D. regimen

Remacemide hydrochloride is a low-affinity, non-competitive N -methyl- D -aspartic acid (NMDA) receptor channel blocker, under investigation in epilepsy. This double-blind, placebo-controlled, multicentre study assessed the safety and efficacy of remacemide hydrochloride or placebo, as adjunctive therapy, in 252 adult patients with refractory epilepsy who were already taking up to three antiepileptic drugs (including an enzyme-inducer). Patients were randomized to one of three doses of remacemide hydrochloride (300, 600 or 1200 mg /day) or placebo Q.I.D., for up to 15 weeks. An increasing percentage of responders (defined as a reduction in seizure frequency from baseline of ≥50%) was seen with increasing remacemide hydrochloride dose. At 1200 mg /day, 23% of patients were responders compared with 7% on placebo. This difference was significant (P= 0.016), as was the overall difference between treatments (P= 0.038). Adverse events: dizziness, abnormal gait, gastrointestinal disturbance, somnolence, diplopia and fatigue were mild or moderate in severity. Carbamazepine and phenytoin plasma concentrations were well controlled and maintained within target ranges, with no evidence of improved seizure control due to increases in the concentrations of these drugs. A dose-dependent, significant, increase in responders following adjunctive remacemide hydrochloride compared with placebo was observed. Remacemide hydrochloride was well tolerated.

Remacemide hydrochloride as an add-on therapy in epilepsy: a randomized, placebo-controlled trial of three dose levels (300, 600 and 800 mg / day) in a B.I.D. regimen

Remacemide hydrochloride is a low-affinity, non-competitive NMDA receptor channel blocker under investigation for the treatment of epilepsy.This double-blind, placebo-controlled, multicentre study assessed the safety and efficacy of adjunctive remacemide hydrochloride or placebo, in adult patients with refractory epilepsy who were already taking up to three antiepileptic drugs (including an enzyme-inducer). Patients (n= 262) were randomized to one of three doses of remacemide hydrochloride (300, 600 or 800 mg/day) or placebo, in a B.I.D. regimen, for up to 14 weeks. Plasma concentrations of carbamazepine (CBZ) and phenytoin (PHT) were controlled throughout. Patients recorded their seizures on a diary card.There was an increase in the percentage of responders (defined as a reduction in seizure frequency from baseline ≥ 50 %), from 15 %(9/60) with placebo, to 30% (18/60) in the 800 mg/day group. A pairwise comparison between remacemide hydrochloride 800 mg/day and placebo was statistically significant (P= 0.049). Most reported adverse events (mainly CNS and gastrointestinal) were mild or moderate in severity and dose-dependent.Adjunctive remacemide hydrochloride treatment was associated with a higher, dose-related responder rate compared with placebo. The difference reached significance at the highest dose tested (800 mg/day). Remacemide hydrochloride was well tolerated.

Clinical significance of the cytochrome P450 2C19 genetic polymorphism.

Cytochrome P450 2C19 (CYP2C19) is the main (or partial) cause for large differences in the pharmacokinetics of a number of clinically important drugs. On the basis of their ability to metabolise (S)-mephenytoin or other CYP2C19 substrates, individuals can be classified as extensive metabolisers (EMs) or poor metabolisers (PMs). Eight variant alleles (CYP2C19*2 to CYP2C19*8) that predict PMs have been identified. The distribution of EM and PM genotypes and phenotypes shows wide interethnic differences. Nongenetic factors such as enzyme inhibition and induction, old age and liver cirrhosis can also modulate CYP2C19 activity. In EMs, approximately 80% of doses of the proton pump inhibitors (PPIs) omeprazole, lansoprazole and pantoprazole seem to be cleared by CYP2C19, whereas CYP3A is more important in PMs. Five-fold higher exposure to these drugs is observed in PMs than in EMs of CYP2C19, and further increases occur during inhibition of CYP3A-catalysed alternative metabolic pathways in PMs. As a result, PMs of CYP2C19 experience more effective acid suppression and better healing of duodenal and gastric ulcers during treatment with omeprazole and lansoprazole compared with EMs. The pharmacoeconomic value of CYP2C19 genotyping remains unclear. Our calculations suggest that genotyping for CYP2C19 could save approximately 5000 US dollars for every 100 Asians tested, but none for Caucasian patients. Nevertheless, genotyping for the common alleles of CYP2C19 before initiating PPIs for the treatment of reflux disease and H. pylori infection is a cost effective tool to determine appropriate duration of treatment and dosage regimens. Altered CYP2C19 activity does not seem to increase the risk for adverse drug reactions/interactions of PPIs. Phenytoin plasma concentrations and toxicity have been shown to increase in patients taking inhibitors of CYP2C19 or who have variant alleles and, because of its narrow therapeutic range, genotyping of CYP2C19 in addition to CYP2C9 may be needed to optimise the dosage of phenytoin. Increased risk of toxicity of tricyclic antidepressants is likely in patients whose CYP2C19 and/or CYP2D6 activities are diminished. CYP2C19 is a major enzyme in proguanil activation to cycloguanil, but there are no clinical data that suggest that PMs of CYP2C19 are at a greater risk for failure of malaria prophylaxis or treatment. Diazepam clearance is clearly diminished in PMs or when inhibitors of CYP2C19 are coprescribed, but the clinical consequences are generally minimal. Finally, many studies have attempted to identify relationships between CYP2C19 genotype and phenotype and susceptibility to xenobiotic-induced disease, but none of these are compelling.

Conventional anticonvulsant drugs in the guinea-pig kindling model of partial seizures: effects of acute phenytoin

This study addressed some of the controversial issues surrounding the anticonvulsant effect of phenytoin, and the predictive validity of the guinea-pig kindling model for the screening of anticonvulsant drugs. Following an intraperitoneal injection of either 50 or 75 mg/kg phenytoin, we analysed plasma concentrations of phenytoin at various time intervals. Behavioural toxicity was assessed at 0.5 h postinjection using quantitative locomotor tests, as well as scores on a sedation/muscle relaxation rating index. The anticonvulsant efficacy of phenytoin was evaluated from measurements of afterdischarge threshold (ADT), afterdischarge duration (ADD) and behavioural seizure severity at three phases of kindling: non-kindled, kindling acquisition (early and late) and kindled (50+ ADs). ADD and seizure severity were also measured in response to both threshold and suprathreshold kindling stimulation. Plasma levels of phenytoin corresponded to the human therapeutic range at the time of behavioural testing and kindling. Phenytoin did not exert significant adverse effects in guinea-pigs on both the behavioural tests and rating index. Phenytoin increased ADT in non-kindled and kindled guinea-pigs and effectively reduced ADD and seizure severity, indicating that the guinea-pig model correctly predicted phenytoin's anticonvulsant effect. Phenytoin produced reliable anticonvulsant activity in the guinea-pig at threshold stimulation but a somewhat reduced efficacy on seizure severity at suprathreshold stimulation intensities. Kindling in the guinea-pig is a valid model of human partial seizures.

August 28 Highlights

“When taking phenytoin sodium with food, product switches may result in either side effects or loss of seizure control.” Wilder et al. examined food-associated differences in drug concentrations between two phenytoin products in 24 healthy subjects and simulated the impact of switching products with data from epileptic patients. Results suggest product switches may have the adverse effect of causing seizures if phenytoin is taken with food. see page 582 Cook et al. reported that a high-fat meal does not alter phenytoin bioavailability from Dilantin Kapseals. Thus, patients may be instructed to take Dilantin Kapseals without regard to meals. Plasma concentration of phenytoin: fed (open circles) and fasted (filled circles) see page 698 The editorial by Lesser and Krauss notes that these articles point to problems with the generic equivalency policies of the US Food and Drug Administration (FDA). While providing cheaper drugs for patients is laudable, FDA standards do not …

Effects of Paeoniae Radix, a traditional Chinese medicine, on the pharmacokinetics of phenytoin.

Phenytoin (PHT), one of the most widely prescribed antiepileptic drugs, has been reported to be associated with numerous drug-drug interactions. However, there are far fewer reports about the pharmacokinetic interactions between PHT and traditional Chinese medicines (TCMs). Paeoniae Radix (PR), one of the well-known TCMs, is used as an adjunct in some epileptic patients. In the present work, we studied the influences of PR on the pharmacokinetics of PHT in rats to identify the possible interactions between PR and PHT. A single dose of PHT (100 mg/kg) alone or in combination with PR extract (300 mg/kg) was administered by gavage to male SD rats. Serial blood samples of PHT were obtained for up to 24 h post-administration and measured by high-performance liquid-chromatography. The free (unbound) plasma concentrations of PHT were determined by fluorescence polarization immunoassay. The plasma concentrations were used to construct pharmacokinetic profiles by plotting drug concentration-time curves. All data were subsequently processed by the computer program WINNONLIN. Statistical comparisons of pharmacokinetic parameters were performed with the unpaired Student t-test. The mean maximum plasma concentration of PHT was attained 2 h after oral administration of PHT alone and 4-6 h after oral administration of PHT in combination with PR. The plasma level of PHT declined with a half-life of 5.38 h after PHT alone and 4.03 h after PHT and PR given together. No statistically significant differences were obtained in most of the pharmacokinetic parameters (Cmax, AUC, t1/2, MRT and CL/F) and protein binding rates of PHT between the two treatments. However, significant differences in Tmax and Vd/F between groups were noted. The significant increase in Tmax indicated that simultaneous oral administration of PR delayed the absorption of PHT. The delayed absorption of PHT might lead to its slow onset of clinical effect. There were no significant differences in Cmax, AUC, t1/2, MRT and CL/F of PHT between the two groups, showing that PR could not significantly affect the extent of absorption, metabolism and elimination of PHT. No significant difference in protein binding rate was found, indicating that PR might not significantly alter the protein binding of PHT. While a significant decrease in Vd/F was noted, the mechanism underlying the apparently decreased Vd/F of PHT influenced by PR needs further study.

Effect of mild therapeutic hypothermia on phenytoin pharmacokinetics.

The authors examined the effect of mild therapeutic hypothermia on phenytoin pharmacokinetics in 14 patients with brain damage. Each patient was given phenytoin during and after mild therapeutic hypothermia. Plasma concentrations of total phenytoin, unbound phenytoin, and 5-(p-hydroxyphenyl)-5-phenylhydantoin (5-p-HPPH), the major metabolite of phenytoin, were measured. Pharmacokinetic parameters during and after mild therapeutic hypothermia were compared. Plasma concentrations of total and unbound phenytoin were significantly higher during hypothermia than after hypothermia. The area under the plasma concentration-time curve (zero to infinity) was increased by 180% and mean residence time was prolonged by 180% during hypothermia compared with the corresponding values after hypothermia. Moreover, the elimination constant (ke) was decreased by 50% and elimination clearance of phenytoin was decreased by 67% during hypothermia compared with the corresponding values after hypothermia. The plasma concentration of 5-p-HPPH was significantly lower during hypothermia than after hypothermia. These findings suggest that phenytoin metabolism is inhibited by mild therapeutic hypothermia.