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We conducted a 10-center, double-blind trial to compare the efficacy and toxicity of four antiepileptic drugs in the treatment of partial and secondarily generalized tonic-clonic seizures in 622 adults. Patients were randomly assigned to treatment with carbamazepine, phenobarbital, phenytoin, or primidone and were followed for two years or until the drug failed to control seizures or caused unacceptable side effects. Overall treatment success was highest with carbamazepine or phenytoin, intermediate with phenobarbital, and lowest with primidone (P less than 0.002). Differences in failure rates of the drugs were explained primarily by the fact that primidone caused more intolerable acute toxic effects, such as nausea, vomiting, dizziness, and sedation. Decreased libido and impotence were more common in patients given primidone. Phenytoin caused more dysmorphic effects and hypersensitivity. Control of tonic-clonic seizures did not differ significantly with the various drugs. Carbamazepine provided complete control of partial seizures more often than primidone or phenobarbital (P less than 0.03). Overall, carbamazepine and phenytoin are recommended drugs of first choice for single-drug therapy of adults with partial or generalized tonic-clonic seizures or with both.

We describe an improved "high-pressure" liquid-chromatographic assay for simultaneous determination in serum of the five major antiepileptic drugs (ethosuximide, primidone, phenobarbital, phenytoin, and carbamazepine) and N-desmethylmethsuximide (the compound that must be quantitated for therapeutic drug monitoring of the antiepileptic drug methsuximide). Serum protein is precipitated with an acetone solution containing 5-ethyl-5-(p-methylphenyl)barbituric acid as the internal standard. The centrifuged supernate is injected onto the chromatographic column. Drugs and internal standard are eluted at 30 degrees C with mobile phase containing acetonitrile/methanol/phosphate buffer (17/28/55 by vol) at a flow rate of 0.7 mL/min, monitored at 195 nm. Analysis time is about 20 min. Quantitation is by measurement of peak areas. Analytical and absolute recoveries varied from 95 to 104%. Within-day coefficients of variation ranged from 1.6 to 5.4%, between-day CVs from 0.0 to 3.4% in subtherapeutic, therapeutic, and toxic samples. Resolution of therapeutic concentrations of all six drugs was complete. As yet, we have found no drug or drug metabolite that interferes.

Phenytoin pharmacokinetics and biotransformation were studied with stable isotope tracer techniques in six patients before and after addition of phenobarbital. No significant (p less than 0.05) changes in phenytoin serum concentration, clearance, elimination half-life, volume of distribution, or clearance via production of p-hydroxyphenyl-phenylhydantoin or phenytoin dihydrodiol occurred after addition of phenobarbital. Thus, frequent phenytoin serum concentration determinations or a change in phenytoin dosing rate are probably not necessary after adding phenobarbital.

Stable isotope labeling of drugs has been used in human metabolism studies because it eliminates the risk of radiation exposure accompanying use of radioactive tracers. The labeled drug can be measured by gas-chromatographic mass spectrometry (GCMS). However, if reliable pharmacokinetic data are to be obtained, one has to be certain the rate of metabolism of labeled and unlabeled drug is the same, i.e., there is no kinetic isotope effect. To evaluate this for phenobarbital (PB), three humans were infused with a 1:1 mixture of phenobarbital and 1,3-15N2-2-13C-PB. Serum was collected at regular intervals. Concentrations of labeled and unlabeled phenobarbital were determined by GCMS. Within each subject, there was no trend for concentrations of labeled phenobarbital to be higher or lower than concentrations of unlabeled phenobarbital (P greater than 0.90 for all three subjects). There was no difference in the zero time intercepts, distribution and elimination time constants and half-lives, volumes of distribution and central compartment, or clearance of the two forms of phenobarbital. Thus, no isotope effect was found. Published data on other labeled drugs and the likelihood of encountering an isotope effect based on type of isotope and its location in the molecule are discussed.

A method suitable for pulse dosing studies is described for the quantitation by gas chromatography mass spectrometry of phenobarbital (5-ethyl-5-phenylbarbituric acid), p-hydroxyphenobarbital (5-ethyl-5(4-hydroxyphenyl)barbituric acid) and, simultaneously, their (13C15N2)-labeled analogs in serum and urine. Differently labeled analogs are used as internal standards (5-ethyl-5(2,3,4,5-tetradeuterophenyl)-2-(13C)barbituric acid for quantitation of phenobarbital, and 5-ethyl-5(4-hydroxy-3,5-dideuterophenyl)2-(13C)-1,3-(15N2)barbituric acid for p-hydroxyphenobarbital). In the procedure, the chemical work-up of the samples (1.0 ml for serum, 0.5 ml for urine) is based on an extractive methylation technique for the generation of the permethylated derivatives. The mass spectrometric measurement technique consists of repetitive scanning over a preselected mass region of the permethylated derivatives of the analytes as they elute from the gas chromatograph. The method is evaluated for serum concentrations ranging from 0.1-30.0 micrograms ml-1 for phenobarbital and 0.1-10.0 micrograms ml-1 for p-hydroxyphenobarbital, and for urine concentrations of both phenobarbital and p-hydroxyphenobarbital of 1.0-50.0 micrograms ml-1. Application of the method to determination of the pharmacological equivalence of phenobarbital and (13C15N2)-labeled phenobarbital in man is also demonstrated.

Six healthy adults receiving no other medications were given tracer doses of 90 mg of stable isotope-labeled phenobarbital (PB) intravenously before, and four weeks after, and 12 weeks after beginning therapy. Serum samples were collected for 96 hours after each injection, and the concentration of stable isotope-labeled PB in each sample was determined by gas chromatographic mass spectrometry. The volume of distribution, elimination half-life, and total clearance of PB did not differ significantly on any of the three occasions measured. Phenobarbital clearance did not correlate significantly with total PB serum concentration. Clearances determined from single-dose studies before beginning PB therapy accurately predicted steady-state PB serum concentrations. Therefore, it is not necessary to adjust PB dosage for time-dependent or dose-dependent changes in clearance during monotherapy. In addition, clearance or serum concentration determined at one dosing rate directly predicts serum concentration at another dosing rate.

Stable isotope labeled tracer doses of phenytoin (PHT) and phenobarbital (PB) were given intravenously before and four and 12 weeks after beginning monotherapy in two groups of six patients. Phenytoin demonstrated nonlinear pharmacokinetics, while PB demonstrated linear pharmacokinetics. Each of the 36 sets of tracer dose serum concentration versus time data points appeared linear during the elimination phase on semilog plots, and each demonstrated a high degree of linearity using semilog regression analysis (r2 = .977-.999, P less than .001, for PHT; r2 = .791-.996, P less than .005, for PB). We conclude tracer doses administered at steady-state serum concentration will exhibit linear serum concentration versus time relationships on semilog plots regardless of whether the steady-state serum concentration is in the linear or the nonlinear portion of a drug's dose versus steady-state serum concentration relationship. The mechanism and implications of this conclusion are discussed.