A nineteen-year-old man with altered mental status.
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Acetazolamide↗
Biomedical subjects
T R Browne
Publications and source records attributed to T R Browne.
Bioavailability studies of drugs with nonlinear pharmacokinetics: I. Tracer dose AUC varies directly with serum concentration.
The authors show that for a drug cleared by one enzyme the area under the serum concentration-time curve from time 0 to infinity (AUC0-INF) of a test dose can be expressed as AUC0-INF = TD x F x (Km + C)/Vmax where TD is test dose size, F is fraction absorbed, C is drug serum concentration at the time of the study, and Km and Vmax are the Michaelis constant and maximum velocity of the enzyme. This equation predicts the AUC0-INF produced by a given tracer dose of drug will vary directly with C in drugs with nonlinear pharmacokinetic properties (i.e., drugs whose value for C approaches or exceeds Km) if C is held constant by administration of tracer and maintenance doses of drug. The AUC0-INF produced by intravenous tracer doses of 150 mg of 13C15N2-sodium phenytoin was determined in 15 subjects at 30 different values of C. AUC0-INF showed a high degree of direct linear correlation with C (AUC0-INF (ug x hr/mL) = 35.4 + 8.1 x C (ug/mL), r = 0.885, P < .0001). Consequences of this observation for relative bioavailability studies of drugs with nonlinear pharmacokinetic properties are discussed.
Adolescent↗
Chronic benzodiazepine administration. IX. Attenuation of alprazolam discontinuation effects by carbamazepine.
Clinical studies suggest that carbamazepine may attenuate effects of alprazolam discontinuation. Since discontinuation of chronic alprazolam in a mouse model is associated with behavioral alterations and upregulation at the gamma-aminobutyric acidA (GABAA) receptor, we studied the effects of carbamazepine administration after alprazolam (2 mg/kg/day) discontinuation. Open-field activity was increased in mice 4 days after alprazolam discontinuation, but this effect was reduced significantly by continuous infusion of carbamazepine, 25 or 100 mg/kg/day. Benzodiazepine receptor binding in vivo was increased in cortex at 2 and 4 days after alprazolam discontinuation, and in hypothalamus at 4 days; with carbamazepine, 100 mg/kg/day, binding in both regions at these time points was similar to control values. Similar results were observed in cortex with benzodiazepine receptor binding in vitro. GABA-dependent chloride uptake was also increased at 4 days alprazolam administration. Treatment with carbamazepine attenuated (P less than 0.10) this increase. Carbamazepine alone after vehicle did not alter benzodiazepine binding or GABA-dependent chloride uptake. These results indicate that carbamazepine administration after alprazolam discontinuation attenuates behavioral and neurochemical alterations associated with discontinuation.
Alprazolam↗
Sensitivity analysis of the effect of bioavailability or dosage form content on mean steady state phenytoin concentration.
Stochastic simulations were used to examine the sensitivity of mean phenytoin steady state concentrations (Css) to changes in the effective dosing rate produced by differences in average product content or bioavailability. Changes of +/- 4%, +/- 6%, +/- 8% and +/- 10% in the effective dosing rate (based on a starting dose yielding a Css of 15 mg/L) were examined. Monte Carlo simulations were performed for each change in dosing rate assuming a one-compartment open model with parallel Michaelis-Menten and first-order elimination. Parameter sets were comprised of a combination of values for maximal rate of saturable elimination (410 or 510 mg/day), the concentration at which the rate of saturable elimination is half maximum (Km, 4.4 or 5.7 mg/L), and linear clearance (CL, 0.15 or 1.5 L/day). These parameters were assumed to be log-normally distributed with coefficients of variation of 30%, 50%, and 15%. The percentages of "individuals" who would be predicted to have Css of less than 10 mg/L following a reduction in the effective dosing rate increased with decreasing Km and CL values. For a Km of 5.7 mg/L and CL of 1.5 L/day, 5% of the "individuals" had Css values of less than 10 mg/L with an 8% decrease in the dosing rate. If the dosing rate was reduced by 10%, then 14-16% of the "individuals" were predicted to have concentrations of less than 10 mg/L. All other combinations of Km and CL values yielded higher percentages of "individuals" with Css of less than 10 mg/L.(ABSTRACT TRUNCATED AT 250 WORDS)
Biological Availability↗
Test performance characteristics of the serum phenytoin concentration (SPC): the relationship between SPC and patient response. The Veterans Administration Epilepsy Cooperative Study Group.
A retrospective analysis of Veterans Administration (VA) Cooperative Study No. 118 was conducted to examine the relationship between serum phenytoin concentration (SPC) and various measures of patient response in 111 patients on monotherapy, mostly after 12 months of treatment. Using patient response rating scales specifically developed and validated for the VA study, we plotted SPC vs overall composite score as well as vs each of the three component ratings of neurotoxicity, systemic toxicity, and seizure type and frequency. No statistically significant association was noted between SPC and any of the response measures. We also calculated test performance characteristics for using SPC and a therapeutic range of 10-22 micrograms/ml to categorize patient status with regard to overall response, toxicity, and seizure frequency. Test sensitivities (0.13-0.53), specificities (0.62-0.81), and positive predictive values (0.08-0.44) were much lower than desirable. This results in a large proportion of false-positive and false-negative errors associated with the use of SPC as a test. Our retrospective evaluation suggests that the range of SPC values in successfully treated patients is quite broad; the value of the commonly accepted SPC therapeutic range in predicting various measures of patient response is quite limited; and patient response, therefore, should be the ultimate end point in monitoring patients on phenytoin. Prospective studies of the relationship between SPC and response should be conducted.
Double-Blind Method↗
Multicenter long-term safety and efficacy study of vigabatrin for refractory complex partial seizures: an update.
We followed 66 patients with refractory complex partial seizures and a favorable initial response to vigabatrin for 5 to 72 (median, 43) months. Thirty-seven patients discontinued vigabatrin for the following reasons: benefit-to-risk evaluation, 8; seizure breakthrough, 6; adverse events, 6; seizure breakthrough and adverse events, 5; moved or lost, 4; no longer eligible for study, 2; non-drug-related death, 2; narcotic abuse, 1; and patient request, three. There were no clinically significant abnormalities in laboratory studies including SMA 12, complete blood count, ECG, EEG, and visual evoked response testing, and no toxicity other than reversible, dose-dependent side effects. Based on this and other long-term data, clinical trials of vigabatrin have resumed in the United States and Canada.
Aminocaproates↗
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.
Absorption↗
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. Baseline resolution of extracted serum containing 2H10 CBZ, CBZ, 2H10 PHT, PHT and IS is achieved on a heated (55 degrees C) 25 cm x 4.6 mm BioAnalytical Systems Phase II 5 microns ODS column with an isocratic mobile phase consisting of water-acetonitrile-tetrahydrofuran (80:16:4, v/v/v) at 1.2 ml/min. Eluting compounds were monitored at a UV wavelength of 214 nm. Calculated resolution of 2H10 CBZ from CBZ and of 2H10 PHT from PHT were 1.3. Serum standard curves were linear (R greater than or equal to 0.999) over a range of 0.5-14 micrograms/ml for 2H10 CBZ, 0.5-20 micrograms/ml for CBZ, 0.5-20 micrograms/ml for 2H10 PHT, and 0.5-30 micrograms/ml for PHT. Within-day percent relative standard deviations (precision) were less than 6% in all cases.
Carbamazepine↗
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. The mobile phase consisted of water-dioxane-tetrahydrofuran (80:15:5, v/v/v) at 2 ml/min and at 50 degrees C, with detection at 225 nm. Baseline separation was achieved by use of a 16 cm x 3.9 mm Nova-Pak C18 column and total analysis time of 12 min. p-HPPH and m-HPPH concentrations ranged from 10 to 200 and from 2 to 30 micrograms/ml, respectively, with between-day coefficients of variations of 3.3-4.5% and 2.2-5.1% for controls. All standard curves were linear with r values greater than 0.993. The DHD concentration was determined by multiplying m-HPPH concentrations by 2.3.
Chromatography, High Pressure Liquid↗
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.
Humans↗
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. 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.
Half-Life↗
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. No significant (P less than .05) "deep pool" effect was detected.
Carbon Radioisotopes↗
Generic substitutions for antiepileptic drugs.
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Anticonvulsants↗
Rarity of EEG photo-paroxysmal and photo-myogenic responses following treated alcohol-related seizures.
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Alcoholism↗
Stable isotopes in clinical pharmacokinetic investigations. Advantages and disadvantages.
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Animals↗
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.
Anticonvulsants↗
A pharmacokinetic rationale for three times daily administration of ethotoin (Peganone).
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Drug Administration Schedule↗
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 median number of CPS per month decreased from 11.0 to 5.0 after addition of GVG, and 51% of patients had a 50% or greater decrease in CPS frequency (P less than 0.001). 3. Side effects (principally drowsiness, ataxia, headache) occurred mainly during the initiation of therapy and decreased during therapy. After 12 weeks on GVG side effects significantly interfered with functioning in only 13% of patients, and the efficacy: toxicity ratio warranted continued administration in 74% of patients. 4. Co-administration of GVG resulted in a mean decrease of 20% in phenytoin serum concentration (P less than 0.001). 5. Sixty-six patients having a favourable response to GVG during the single-blind study have been followed for 6-54 (median 33) months on GVG. Only 17 patients have dropped out of long-term follow-up due to break through seizures and/or side effects. No serious systemic or neurological toxicity has been detected.
Adult↗