Folic acid improves phenytoin pharmacokinetics.

Phenytoin (PHT) therapy to control seizures decreases serum folate levels in half of epileptic patients, thus increasing the risk of folate depletion. Supplementation with folic acid prevents deficiency but also changes PHT pharmacokinetics. Kinetic monitoring of PHT when folic acid is provided as a supplement has not been reported in women of child-bearing age. This study of six fertile women examined the interdependence of PHT and folic acid in a randomized crossover study of two treatments: treatment 1 consisted of 300 mg sodium PHT per day and treatment 2 consisted of 300 mg sodium PHT plus 1 mg folic acid per day. Dietary folic acid intake was calculated daily. During treatment 1, serum folate level decreased 38.0 +/- 18.6% (mean +/- standard deviation) and serum PHT concentration was in the low therapeutic range (43.92 +/- 14.52 mumol/L). During treatment 2, serum folate level increased 26.0 +/- 33.4%, and serum PHT level (39.04 +/- 14.16 mumol/L) was similar to that in treatment 1. Only one subject attained PHT steady state during treatment 1, but four subjects achieved steady state during treatment 2. Dietary folate intakes during treatments 1 and 2 were not significantly different. This study suggests an interdependence between PHT and folic acid and supports the observation that fertile women treated with PHT require folic acid supplementation to maintain a normal serum folate level.

Phenobarbital removal characteristics of three brands of activated charcoals: a system analysis approach.

The in vivo phenobarbital removal characteristics of three brands of activated charcoal (Actidose, Charcoaid, Superchar) were studied in normal volunteers using a system analysis approach. The subjects received a 200-mg dose of oral or intravenous phenobarbital followed by a single oral dose of 30 g of one of the three charcoals in a randomized crossover design. The relative merits of the three charcoals in enhancing the removal of oral and intravenous phenobarbital were assessed using a system analysis approach. The removal clearance, time to peak (tp), peak removal clearance (Rmax), percentage of dose removed (PCT infinity), and phenobarbital removal clearance (CLr) were calculated for the oral and intravenous treatments. Superchar had a pulse-like effect, with the shortest tp and the largest Rmax. Actidose and Charcoaid had similar effects, with Actidose inducing slightly greater phenobarbital removal. Superchar has the highest surface area and relative percentage of surface hydroxyl groups, whereas Actidose has the lowest surface area and relative percentage of surface hydroxyl groups of the three charcoals studied. Although correlations between the in vitro and the in vivo phenobarbital adsorption characteristics of the three charcoals may be difficult due to the presence of preservatives and palatibility enhancers in the commercial preparations, it appears that the in vivo effectiveness decreases as the surface area and the concentration of surface hydroxyl groups decrease. The proposed system analysis approach requires fewer assumptions than methods based on compartmental or physiologic approaches and has the advantage of describing the phenobarbital removal in a dynamic manner.

Phenytoin pharmacokinetics: before and after folic acid administration.

Phenytoin (PHT) exhibits linear and Michaelis-Menten pharmacokinetics. PHT decreases serum folate; the vitamin folic acid (FA) is hypothesized to be a cofactor in the metabolism of PHT. The depletion of serum folate may explain the unpredictability of measured total serum PHT concentrations and time to steady state as compared with the Michaelis-Menten predictive calculations. We examined PHT pharmacokinetics before and after FA supplementation in 13 healthy male volunteers. The study was divided into two phases. Phase I determined V(max) (mg/day) and Km (micrograms/ml) of PHT to calculate PHT doses needed for the second phase. Phase II was a four-way cross-over study to examine the effect of 1 and 5 mg FA on total serum PHT concentrations 1 microgram/ml less and 5 micrograms/ml greater than the subject's Km, Km - 1 and Km + 5, respectively. Predicted versus measured total serum PHT concentrations, t90% (days to steady state), and the effect of FA were calculated for Km - 1 and Km + 5 before and after 1 or 5 mg FA. The measured total serum PHT concentration was always greater than the calculated concentration (p less than 0.05), and t90% was always longer than the calculated t90% (p less than 0.05) for Km - 1 before FA (all subjects decreased serum FA); the same was observed for Km + 5. If folate is assumed to be a cofactor in PHT metabolism, these results are expected, because depletion of the vitamin would indicate less folate to drive the metabolism of PHT, resulting in higher total serum PHT concentrations and longer time to reach steady state.(ABSTRACT TRUNCATED AT 250 WORDS)

Surface characterization of activated charcoal by X-ray photoelectron spectroscopy (XPS): correlation with phenobarbital adsorption data.

X-ray photoelectron spectroscopy (XPS) was used to identify the functional states of carbon existing on the surfaces of various activated charcoals. The relative percentages of carbon, oxygen, and detectable trace elements comprising the activated charcoal surfaces were determined. Analysis of the carbon core-electron binding energy region revealed the existence of one hydrocarbon state (C-H, C-C are indistinguishable) and three oxygen-containing functional states. These states were hydroxyls or ethers (C-O), carbonyls (C = O), and carboxylic acids or esters (O-C = O). The C-O functional state contributed approximately 60-70% to the total percentage of oxygen-containing states. A very good correlation existed between the apparent areas occupied on the adsorbent surface per phenobarbital molecule and the relative percentages of the C-O functional state. Previously reported heat of displacement results for phenobarbital adsorption are now explained since the C-O state appears to be the primary site involved in the binding of phenobarbital by the activated charcoals.

Model selection for the adsorption of phenobarbital by activated charcoal.

Activated charcoal is known to adsorb a wide variety of substances from solution, and several equations have been used to fit the resulting adsorption data. The determination of the correct model to fit phenobarbital adsorption onto activated charcoal was made using a calorimetric method. The differential heats of displacement of water by phenobarbital for four activated charcoals were determined and found to be linearly related to the amount of phenobarbital adsorbed. The activated charcoals studied had statistically similar heats of displacement. The linear relationship between heat evolved and the amount of phenobarbital adsorbed is consistent with the assumptions implicit in the Langmuir model.

Phenobarbital adsorption from simulated intestinal fluid, U.S.P., and simulated gastric fluid, U.S.P., by two activated charcoals.

Adsorption of phenobarbital from simulated intestinal and gastric fluids by two activated charcoals was studied. Adsorption isotherm data were analyzed by the linearized Langmuir equation and by nonlinear least-squares regression employing both Langmuir and Freundlich models. These analyses indicated differences in the capacities of the two charcoals for phenobarbital which could not be completely explained by surface-area considerations.

Decrease of serum folates in healthy male volunteers taking phenytoin.

The effect of phenytoin (PHT) on serum folate and the effect of additional oral folic acid (FA) on serum folate during continued treatment with PHT were studied in 13 healthy male subjects 20-35 years of age. The study was divided into two phases: Phase I determined Vmax (mg/kg/day) and Km (microgram/ml) of PHT in order to calculate the PHT doses needed for the second phase. Phase II was a four-way cross-over study to examine the effect of 1 and 5 mg FA on total serum PHT concentrations 1 microgram/ml less and 5 micrograms/ml greater than the subject's Km, Km-1 and Km+5, respectively. Both phases examined the effect of PHT on serum folate. In Phase I, serum folate decreased by a mean and standard deviation of 42.15 +/- 21.44% after an average of 24.15 +/- 5.63 days of PHT administration, with a mean steady-state total serum PHT concentration of 8.45 +/- 2.70 micrograms/ml. Mean percentage decreases in serum folate before the addition of 1 and 5 mg FA in Phase II were 12.80 +/- 31.45% and 23.24 +/- 21.24% for Km-1 and Km+5, respectively. The average numbers of days of PHT administration and total serum PHT concentrations before FA administration were 9.52 +/- 3.34 and 15.84 +/- 7.02 days, and 2.60 +/- 2.18 and 8.64 +/- 3.44 micrograms/ml, for Km-1 and Km+5, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Phenytoin binding in healthy volunteers.

The pharmacologic effect of phenytoin is directly related to the unbound concentration in the serum, which previously has been reported in the literature to be approximately 10%. The results of 13 out of 14 20-35 year-old healthy male volunteers studied indicate that less than 10% unbound phenytoin is present in the majority of subjects taking two different doses of phenytoin.

Utilization of Km for phenytoin dosage after folate addition to patient regimen.

Phenytoin decreases serum and red blood cell folates in 50% of the patients on the anticonvulsant. The supplementation of folic acid changes the disposition of phenytoin, a drug that exhibits Michaelis-Menten kinetics. In a retrospective study at the Veterans Administration Medical Center, seven adult male folate-deficient epileptic patients on phenytoin alone and compliant with the anticonvulsant were supplemented with 1 mg oral folic acid. Before and after the addition of the vitamin, Vmax and Km were calculated for phenytoin. With folic acid, the total serum phenytoin concentration decreased significantly by an average of 22.6 +/- 13.0%. The Km decreased significantly from 6.7 +/- 1.1 to 4.1 +/- 1.5 micrograms/ml. The Vmax remained unchanged. It is hypothesized that folic acid is a cofactor in the metabolism of phenytoin. A cofactor would be expected to alter the affinity (Km) of the enzymes for phenytoin with no change in the liver's total capacity (Vmax) to metabolize phenytoin. This retrospective study in seven male epileptic patients is a convincing argument for the hypothesis.

Parkinsonism--drug treatment: Part II.

This article, second in a two-part review, discusses investigational drug therapy and miscellaneous drug management of parkinsonism. Drug therapy should be individualized according to signs and changed as the disease progresses or if the patient develops intolerable side effects. Investigational drugs being examined include sustained-release and injectable dopaminergic formulations. Drug-induced parkinsonism is also examined.

Parkinsonism--drug treatment: Part I.

The purpose of this two-part review is to explain current drug treatment in part I and discuss investigational drug therapy and miscellaneous drugs in the management of parkinsonism in part II. The medical approach to this disease is still based on the imbalance between a deficiency of dopamine and a functional increase in acetylcholine. Anticholinergic agents are used to treat the tremors in the early stages of the disease.

Effect of charcoal and sorbitol-charcoal suspension on the elimination of intravenous phenobarbital.

The effects of two different oral charcoal suspensions on the elimination of a 200 mg/70 kg, 1 h intravenous (i.v.) infusion of phenobarbital and the tolerances of the two regimens were determined in a randomized crossover study in six healthy male volunteers. Phenobarbital was given i.v. alone or together with 105 g of oral activated charcoal suspension or with 105 g of a commercially available sorbitol-charcoal suspension over a 36-h period. A 13-34% decrease in the area under the serum concentration time curve (AUC) for 0-60 h occurred with the administration of the activated charcoal, and a 19-52% decrease occurred with the commercial sorbitol-charcoal regimen. The mean apparent systemic clearance of total phenobarbital increased from 0.089 +/- 0.019 ml/min/kg to 0.141 +/- 0.029 and 0.146 +/- 0.036 ml/min/kg with the charcoal and sorbitol-charcoal treatments, respectively. No significant change in the fraction of phenobarbital bound to protein was detected. The charcoal regimen caused constipation in one subject. All subjects taking the sorbitol-charcoal preparation experienced diarrhea; there were no changes in electrolytes with either charcoal suspension. All subjects preferred the sorbitol-charcoal preparation.

Linear systems approach to the analysis of an induced drug removal process. Phenobarbital removal by oral activated charcoal.

The theory of linear systems analysis is applied to the evaluation of induced drug removal processes. The rate and extent of removal are determined by deconvolution for the case of phenobarbital removal from the systemic circulation by orally administered activated charcoal. The proposed method is model independent in the sense that no specific models of intrinsic or induced pharmacokinetic processes are required, and it is readily adapted to the analysis of most types of induced removal processes (hemodialysis, peritoneal dialysis, etc.). Application of the approach indicates that phenobarbital was removed from the systemic circulation to an extent of 25-53% following multiple oral doses of activated charcoal in healthy human subjects.

Phenytoin-folic acid: a review.

The nutrient-drug interaction between folate and phenytoin is a two-way interaction. Folate deficiency resulting from long-term phenytoin therapy is a common occurrence, but progression of the deficiency to a megaloblastic anemia is rare. However, there are data to suggest nonanemic folate deficiency may be detrimental to the patient. Several mechanisms have been proposed to explain the ability of phenytoin to deplete body folate. The supplementation of folic acid to folate-deficient patients taking phenytoin has been shown to result in lowered serum concentrations of phenytoin, and possibly loss of control of the seizure disorder. Folate appears to be associated with the hepatic metabolism of phenytoin, although the effect of folic acid supplementation on phenytoin elimination kinetics is suggested to be individualized.

Phenytoin and folic acid interaction: a preliminary report.

The effect of folic acid (1 mg/day orally) on phenytoin steady-state pharmacokinetics was studied in four male folate-deficient epileptic patients who were treated with only one anticonvulsant. Each patient served as his own control before and after starting folic acid replacement therapy. The Michaelis-Menten parameters, Vmax and Km, were calculated for each patient, and compliance with the single anticonvulsant drug (phenytoin) regimen was documented. Blood and urine samples were collected just before (day 1) and after 180 or 300 days of vitamin administration. Total and free phenytoin were measured in plasma; and phenytoin, 5-(p-hydroxyphenyl)-5-phenylhydantoin (p-HPPH), 5-(3,4-dihydroxyphenyl)-5-phenylhydantoin (DHD) were measured in 24-h urine. After the addition of folic acid, total phenytoin plasma concentration decreased 7.5-47.6% in three of the four patients, and the extent of this change correlated with Km (r2 = 0.99). Ratios of urinary metabolites to parent drug increased in those patients showing a decrease in plasma phenytoin caused by folic acid supplementation. This indicated that a folic acid-associated increase in phenytoin oxidative metabolism had occurred.

Optimization of pharmacokinetic monitoring: I. Linear pharmacokinetics.

To reach and maintain therapeutic drug concentrations, reliable estimates of the parameters describing the pharmacokinetic behavior of the drug are required. The accuracy and precision of the pharmacokinetic parameters are dependent upon the error associated with the time of specimen collection and the laboratory assay error. In this report, the determinate error and random error are analyzed independently and incorporated in calculations of regimens of two drugs, gentamicin and theophylline. The calculations show that, within a particular concentration range, there are better times for sampling to determine the elimination rate constant and, consequently, the dose. From the generalized, first-order equation for a one-compartment pharmacokinetic model, ln Ct = ln C0 - Kt, where C = plasma drug concentration, t = time, C0 = C at zero time, and the elimination rate constant, K = 0.693/t1/2, the determinate error, epsilon K, in K is epsilon = (1/C0t)epsilon C0 - (In C0/C)t-2 epsilon t, and the random error, assuming a gaussian distribution, is (formula; see text) where S2x is variance of parameter x. Therefore, the variances of the calculated quantity, C0, the measured quantity, C, and the time of sample collection, t, are initially of equal importance. However, with increasing t, the effect of S2t becomes small. In both random and determinate error cases, increased time of sampling after dose reduces the error in K, thus t1/2, as do recognized biological factors. However, increased relative analytical error may obliterate this advantage if analyses are not modified to obtain best quantitation at low, even subtherapeutic concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Phenytoin and folic acid: individualized drug-drug interaction.

The effect of folic acid supplementation on the disposition of phenytoin and the resultant loss of seizure control in a male folate-deficient epileptic is reported. Due to the increase in tonic-clonic seizures after the initiation of folic acid (1 mg, orally) the sodium phenytoin dosage was increased by 130 mg until control was achieved. Because of these dosage changes, the Vmax and Km were calculated before and after initiation of the folic acid. The Vmax remained relatively the same, but the Km decreased after folate supplementation.

Electroencephalographic absence status with minimal behavior change.

Difficulty in correlating EEG abnormalities with clinical seizures is emphasized in this case report of an epileptic patient with electrical status epilepticus and normal behavior. In addition, the usefulness of dichotic listening tests in the identification of subtle perceptive and expressive impairments is illustrated in this same patient at a time of noncompliance with anticonvulsant therapy.

Decreased phenytoin levels in antineoplastic therapy.

A case history is reported illustrating the difficulties which may be encountered in maintaining seizure control in patients being treated with antineoplastic therapy. The maintenance of therapeutic serum levels of phenytoin during combined cis-platinum and bleomycin sulfate therapy suggests an absorptive defect, possibly related to damage of the intestinal mucosa. This defect did not appear to alter the absorption of primidone or phenobarbital, since increased dosages were not necessary to maintain these drugs within therapeutic ranges.