Microscale ultrafiltration technique for determining free drug in 50-microL serum samples.
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Abstract This ultrafiltration technique allows determination of free drug in 50 microL of serum. We ultrafiltered sera containing the following drugs--valproic acid (and its major metabolites), phenobarbital, diazepam, indomethacin, phenytoin, furosemide, and chloramphenicol--using both the commercially available micropartition system (MPS-1, Amicon), which requires a 200-microL sample, and our modified micro system, which requires only 50 microL. The value for the free fraction of each drug obtained in the two experiments agreed well. The smaller sample requirement makes the micro method particularly suited for pediatric samples and studies on small laboratory animals.Keywords:
Ultrafiltration (renal)
Free fraction
Phenobarbital
Valproic Acid
Primidone
Phenobarbital
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The anticonvulsant properties of phenobarbital and phenytoin given individually or in various combinations were determined by the maximal electroshock seizure test in rats 2 hours after subcutaneous administration. Drug concentrations in brain and plasma obtained immediately after maximal electroshock seizure were measured by gas-liquid chromatography. Total brain anticonvulsant drug concentrations required to abolish the hindlimb extensor component of maximal electroshock seizure were similar when these drugs were employed singly or in combinations. The median effective brain concentrations (EC50) were: phenobarbital, 12.2 micronmol/kg; phenytoin 12.3 micronmol/kg; and phenobarbital plus phenytoin, 14.8 micronmol/kg. Brain/plasma concentration ratios of these drugs were not affected by concomitant administration of the other agent: phenobarbital alone, 0.73; phenobarbital in the presence of phenytoin 0.77; phenytoin, 1.21; and phenytoin in the presence of phenobarbital, 1.22. Brain and plasma concentrations of phenytoin relative to the dose employed were significantly higher (P less than .001) when phenobarbital was administered concurrently than when phenytoin was given alone. This resulted in an apparent potentiation of anticonvulsant activity at 2 hours when these drugs were administered simultaneously. The anticonvulsant activity of the two combinations could be accounted for by the sum of the concentrations of the individual drugs in brain.
Phenobarbital
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The anticonvulsant properties of phenobarbital and phenytoin given individually or in various combinations were determined by the maximal electroshock seizure test in rats 2 hours after subcutaneous administration. Drug concentrations in brain and plasma obtained immediately after maximal electroshock seizure were measured by gas-liquid chromatography. Total brain anticonvulsant drug concentrations required to abolish the hindlimb extensor component of maximal electroshock seizure were similar when these drugs were employed singly or in combinations. The median effective brain concentrations (EC50) were: phenobarbital, 12.2 micronmol/kg; phenytoin 12.3 micronmol/kg; and phenobarbital plus phenytoin, 14.8 micronmol/kg. Brain/plasma concentration ratios of these drugs were not affected by concomitant administration of the other agent: phenobarbital alone, 0.73; phenobarbital in the presence of phenytoin 0.77; phenytoin, 1.21; and phenytoin in the presence of phenobarbital, 1.22. Brain and plasma concentrations of phenytoin relative to the dose employed were significantly higher (P less than .001) when phenobarbital was administered concurrently than when phenytoin was given alone. This resulted in an apparent potentiation of anticonvulsant activity at 2 hours when these drugs were administered simultaneously. The anticonvulsant activity of the two combinations could be accounted for by the sum of the concentrations of the individual drugs in brain.
Phenobarbital
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In 80 epileptics receiving Phenydantin or Phenytoinum the blood levels of phenytoin and phenobarbital were determined. In all, 160 determinations of phenytoin (PHT) and 120 determinations of phenobarbital (PB) were done. Drug levels were determined spectrophotometrically. In 7% of patients toxic concentrations of PHT and in 3% toxic concentrations of PB were found. The PHT level below the therapeutic one was found in 16% of cases, and PB in 23%. The results of this study point to the necessity of routine control of the levels of anticonvulsants in the blood.
Phenobarbital
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Summary The present study investigated order and temporal spacing interactions of phenytoin and phenobarbital in terms of plasma levels during multiple dosing in monkeys. Phenytoin at a dose of 30 mg/kg and phenobarbital at a dose of 3 mg/kg were administered separately to 4 animals (control group) by nasogastric intubution daily for 10 days. In four subsequent 10‐day periods the drugs were administered together in 4 other animals (interaction group) at different times of the day (immediately following one another, 1/2 hr apart, and 6 hr apart) and in a different order of administration (either phenobarbital first and phenytoin later, or the reverse). Blood samples were obtained on the 5th, 8th, and 10th day of each 10‐day period. The plasma data indicated: (a) phenytoin is capable of autoinduction, (b) phenobarbital lowers the levels of phenytoin under the four methods of administration studied here, and (c) phenytoin can affect the levels of phenobarbital. The latter interaction is a function of order and temporal spacing of drug administration.
Phenobarbital
Drug Administration
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THe effects of phenobarbital on the plasma concentration of phenytoin and mortality of the phenytoin-treated mice were mainly studied. The plasma concentration of phenytoin estimated in the live mice after electroshock was significantly higher than that in the dead mice, suggesting that biological activity of phenytoin is dependent on its plasma concentration where individual difference seems to be large. Though the pretreatment of mice with phenobarbital lowered the plasma concentration of phenytoin, all the mice were alive after electroshock with further treatment with phenobarbital and phenytoin. These results suggest that combination of phenobarbital with phenytoin for the treatment of epileptic patients may be feasible.
Phenobarbital
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Eight patients were treated concurrently with a constant dose of phenytoin and valproic acid for 1 year. During initial therapy with valproic acid, total plasma phenytoin levels decreased. The interaction was transient and was not observed at the end of 1 year. Total plasma phenytoin levels returned to pre-valproic-acid levels in seven patients.
Valproic Acid
Plasma levels
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1 Plasma protein binding of phenytoin and of valproic acid were measured in ten epileptic patients on this drug combination. Ten other epileptics not on valproic acid served as controls. All patients had normal kidney function. 2 The measured free fraction of phenytoin among the patients on valproic acid ranged from 12.5 to 23.2% and after recalculation to a plasma albumin level of 45 g/l from 12.5 to 20.0 (median 15.4%). This differed significantly (P = 0.002, Mann- Whitney U-test) from the control patients where the normalized values ranged from 9.9 to 13.9% with a median value of 11.8%. 3 The measured free fractions of phenytoin and of valproic acid showed a significant correlation which, however, was due to the quantitative relation between the degree of binding of both these drugs and the concentration of plasma albumin. There was no discernable relation in this material between the free concentration of valproic acid and the free fraction of phenytoin. 4 It is concluded that patients on combined treatment with phenytoin and valproic acid have an unpredictably raised free fraction of phenytoin. This drug interaction therefore can complicate the important plasma level monitoring of phenytoin in epileptic patients unless the free concentration of this drug can be analysed or estimated.
Valproic Acid
Free fraction
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Primidone
Phenobarbital
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Seizures occur in 1 to 2 percent of neonates admitted to an intensive care unit. The treatment is usually with either phenobarbital or phenytoin, but the efficacy of the two drugs has not been compared directly.
Phenobarbital
Neonatal seizure
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