New pharmacokinetic methods for the study of antiepileptic medications of the 1990s.

New methods that will be useful in the study of the pharmacokinetics of both new and established antiepileptic drugs include stable-isotope tracer techniques for studies of absorption, elimination, and drug interactions; the microperfusion technique and the staggered stable-isotope administration technique for the study of distribution; and the correction of trough drug serum concentration values to mean serum concentration values. New pharmacokinetic methods for a study of drugs with new and unique properties include a double stable-isotope technique to deal with the unique pharmacokinetic properties of prodrugs and techniques for describing the biologic half-life of drugs that have a high affinity for active sites.

Simultaneous determination of p-hydroxylated and dihydrodiol metabolites of phenytoin in urine by high-performance liquid chromatography.

Accurate urinary measurements of the two major metabolites of phenytoin, 5-(p-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) and 5-(3,4-dihydroxy-cyclohexa-1,5-dienyl)-5-phenylhydantoin (dihydrodiol, DHD), are necessary for pharmacokinetic and drug-interaction studies of this commonly used antiepileptic drug. We describe a simple, rapid, acid hydrolysis, with liquid-liquid extraction and simultaneous isocratic reversed-phase high-performance liquid chromatography of p-HPPH and 5-(m-hydroxyphenyl)-5-phenylhydantoin (m-HPPH) (hydrolytic end product of DHD). p-HPPH and m-HPPH were quantitated against their separate respective internal standards of alphenal and tolylbarb.

Simultaneous separation and determination (in serum) of phenytoin and carbamazepine and their deuterated analogues by high-performance liquid chromatography--ultraviolet detection for tracer studies.

The use of stable isotope-labeled tracer compounds is the safest and most effective method to perform many steady state pharmacokinetic and drug interaction studies. We describe a method by which the heavily deuterated 2H10 analogues of carbamazepine (2H10 CBZ) and phenytoin (2H10 PHT) can be chromatographically separated by high-performance liquid chromatography from unlabeled CBZ and PHT. All compounds are quantitated against an internal standard (IS) (10,11-dihydrocarbamazepine) and measured using conventional UV detection rather than mass spectrometry.

New pharmacokinetic methods. III. Two simple test for "deep pool effect".

If a portion of administered drug is distributed into a "deep" peripheral compartment, the drug's actual elimination half-life during the terminal exponential phase of elimination may be longer than determined by a single dose study or a tracer dose study ("deep pool effect"). Two simple methods of testing for "deep pool effect" applicable to drugs with either linear or nonlinear pharmacokinetic properties are described. The methods are illustrated with stable isotope labeled (13C15N2) tracer dose studies of phenytoin.

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.

New pharmacokinetic methods: I. 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.

The pharmacokinetics of agents used to treat status epilepticus.

A thorough understanding of the pharmacologic properties of lipid-soluble drugs is essential when using these agents to treat status epilepticus. In addition to physiologic factors, such as blood pressure and cerebral blood flow, pharmacokinetic principles, including half-life, distribution, elimination, and volume of distribution (with special regard to an agent's lipid-solubility rating), should be applied. These factors, in toto, will influence the choice of drug, its loading dose, and its therapeutic dose.

Time course of carbamazepine autoinduction. The VA Cooperative Study No.118 Group.

We sequentially determined carbamazepine clearance values in 17 patients at the end of weeks 1, 2, 4, 8, and 12 of monotherapy. There were no significant differences among these clearance values. In 11 of 17 patients, week 1 clearance accurately predicted week 12 carbamazepine serum concentration (within +/- 33%).

Bioavailability of ACC-9653 (phenytoin prodrug).

The bioavailability of phenytoin from ACC-9653 versus intravenously administered sodium phenytoin was determined using a crossover design for intravenous and intramuscular administration of ACC-9653 to healthy volunteers. Absolute bioavailability of phenytoin derived from ACC-9653 in each subject was calculated as the ratio of the phenytoin area under the plasma concentration time curve for time 0 to infinity [AUC(0-inf)] after ACC-9653 divided by the phenytoin AUC(0-inf) after intravenous sodium phenytoin. The mean absolute bioavailability of ACC-9653 was 0.

A multicentre study of vigabatrin for drug-resistant epilepsy.

1. Vigabatrin (GVG) was given in a single-blind fashion to 89 patients with complex partial seizures (CPS) refractory to conventional drugs. 2.

The Team Physician Is a Sideline Psychologist.

Being a team physician requires much more than being a good clinician, says the author. It requires understanding the psychology of the players, the coach, and the team as a whole.

Carbamazepine increases phenytoin serum concentration and reduces phenytoin clearance.

Addition of carbamazepine to phenytoin monotherapy resulted in the following significant (p less than 0.05) changes: (1) increased mean phenytoin serum concentration; (2) decreased phenytoin clearance, due to decreased production of phenytoin dihydrodiol and p-hydroxyphenyl-phenylhydantoin; (3) increased phenytoin elimination half-life; and (4) increased drug-related toxicity. Close monitoring is required after addition of carbamazepine to phenytoin.

Pseudomonas osteomyelitis of the metatarsal sesamoid. A case report.

Osteomyelitis of the metatarsal sesamoid is rare. Few cases of Pseudomonas osteomyelitis have been reported. This report includes a current review of the literature and case report.

Phenobarbital does not alter phenytoin steady-state serum concentration or pharmacokinetics.

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.

Determination of the in vivo Km and Vmax of a drug with tracer studies.

A method is described for determining the in vivo Km and Vmax values for a drug, utilizing a variant of the Michaelis-Menten equation and the elimination-rate constants of tracer doses of the drug administered at two different serum concentration values. The new method is the most accurate yet devised; unlike older methods, it is dependent on assumptions that generally are true and can be validated empirically. Application of the method is demonstrated by a study of phenytoin in humans.

Estimation of the elimination half-life of a drug at any serum concentration when the Km and Vmax of the drug are known: calculations and validation with phenytoin.

A method of estimating the elimination half-life of a drug at any selected serum concentration when the Km and Vmax of that drug are known is described. The method was validated in six patients by determining their Km and Vmax values for phenytoin, using data obtained at two serum concentrations and then using the Km and Vmax values to predict the elimination half-life of phenytoin at a third serum concentration. The predicted elimination half-lives at the third serum concentration did not differ significantly (t = 1.