Dorothy D. Schottelius

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), carbon-yls (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.

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.

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.

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.

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 (CAT), and 5–(3, 4-dihydroxy-l, 5-cyclohexadienlyl)-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.

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.

Phenytoin Pharmacokinetics: Before and After Folic Acid Administration

Summary: Phenytoin (PHT) exhibits linear and Michaelis‐Menten pharmacokinetics. PHT decreases serum folate; the vitamin folk 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 1 determined Vmax (mg/day) and Km (μg/ml) of PHT to calculate PHT doses needed for the second phase. Phase 11 was a four‐way cross‐over study to examine the effect of 1 and 5 mg FA on total serum PHT concentrations 1 μg/ml less and 5 μg/ml greater than the subjects Km, K−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 < 0.05), and t90% was always longer than the calculated t90% (p < 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. Even though steady‐state criterion was satisfied, “pseudo‐steady state” could have occurred, making the time to steady state longer and possibly increasing total serum PHT further. When FA was added, the same results were obtained. Neither was there any difference in total serum PHT concentration before and after either 1 or 5 mg FA. These latter results may be explained by the fact that depletion of FA had to be corrected first before the role of FA as a cofactor in PHT metabolism could be used. Therefore, the interdependence of PHT and FA may explain the pseudo‐steady state observed for PHT and the deviations from the Michaelis‐Menten predictive calculations. Perhaps FA supplementation should be recommended when PHT therapy is initiated.

Decrease of serum folates in healthy male volunteers taking phenytoin.

Summary: 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 (μg/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 μg/ml less and 5 μg/ml greater than the subjects 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 μg/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 μg/ml, for Km‐1 and Km+5, respectively. The percentage increases in serum folate after taking FA while continuing PHT in Phase II were as follows: 38.78 ± 72.84%, Km‐1 (1 mg FA): 81.38 ± 72.75%, Km+5 (1 mg FA); 138 ± 93.43%, Km‐1 (5 mg FA); and 169.67 ± 69.67%, Km+5 (5 mg FA). Five milligrams FA increased the serum folate more than the 1‐mg dose. The higher total PHT concentration was associated with a greater decrease in the serum folate. Therefore, serum folate may decrease early with PHT therapy and should be monitored at that time.

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 folk 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 μg/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 phenyloin with no change in the livers total capacity (Vmax) to metabolize phenytoin. This retrospective study in seven male epileptic patients is a convincing argument for the hypothesis.