Influence of food on the absorption of phenytoin in man

Summary The influence of food intake on the absorption of phenytoin was examined in eight healthy volunteers, by study of single-dose kinetics following ingestion of phenytoin 300 mg either with a standardized breakfast or on an empty stomach. Blood samples were collected at regular intervals from 0 to 48 h, and serum concentrations of unmetabolized phenytoin were determined by gas chromatography. Serum concentrations of the major metabolite of phenytoin, 4-hydroxyphenytoin, were measured by mass fragmentography. Concurrent intake of food and phenytoin appeared to accelerate absorption of the drug from the formulation used, and the peak concentrations were significantly higher (mean increase 40%) in the postprandial than in the preprandial state. As reflected by the AUC (area under the curve), the amount of drug absorbed was increased during postprandial conditions, although the difference only reached borderline significance. It is suggested that phenytoin should always be taken in a defined relation to meals.     

The effects of sucralfate upon phenytoin absorption in man.

The possible influence of sucralfate on phenytoin absorption was investigated in a double-blind, placebo controlled study. Concomitant administration of 1 g sucralfate reduced the absorption of 300 mg phenytoin capsules by 20% as measured by the area under the curve from 0-48 h. This could be of significance in epileptic patients stabilised on phenytoin in whom sucralfate is used in ulcer treatment.     

Drastic improvement in the rectal absorption profile of morphine in man

Summary Rectal absorption of morphine HCl from aqueous vehicles at different pHs in man has been compared with an orally administered solution. Plasma concentrations of morphine were measured by electrochemical HPLC analysis after a single dose of 10 mg morphine HCl, in a cross-over study in 7 volunteers. Rectal absorption of morphine was dependent on pH, which could be explained as being due to pH partitioning. The absorption rate and bioavailability could be greatly improved, as compared to orally administered morphine, by adjusting the pH. It was concluded that a rectal solution adjusted to pH 7 to 8 provided an entirely adequate dosage form.     

Reduction of absorption of digoxin,phenytoin and aspirin by activated charcoal in man

Summary The inhibitory effect of activated charcoal 50 g suspended in water on the absorption of digoxin, phenytoin and aspirin was studied in six healthy volunteers in a cross-over manner. The absorption of digoxin and phenytoin were almost completely prevented (about 98%) when activated charcoal was ingested immediately after the drug. The total absorption of aspirin was inhibited by 70%, with clear postponement of absorption and partial release of aspirin from the charcoal in the gut: The peak serum concentration of aspirin was reduced by 95% by charcoal. When activated charcoal was ingested 1 hour after the drugs the inhibition of absorption was considerably less. However, since the absorption of larger doses of the drugs is often slow, the administration of an adequate dose of activated charcoal will be of definite value in the treatment of acute intoxication, even if delayed for several hours.     

The elimination of phenytoin in man

1. Plasma phenytoin (diphenylhydantoin) levels after different drug doses were correlated with urinary 5-(p-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) excretions in four subjects. 2. In three of four subjects the proportion of the phenytoin dose that was excreted as p-HPPH diminished as the dose increased. In the fourth, p-HPPH output remained proportionate to dose of phenytoin until elimination of the drug fell below its input. 3. Plasma p-HPPH levels were measured in two subjects; the data suggested that the renal excretion of p-HPPH was not rate-limited. 4. In three of four subjects, there was the possibility that alternative pathways for eliminating phenytoin may have developed as drug doses increased and the capacity for forming p-HPPH became saturated. 5. Overall phenytoin elimination appeared to approach saturation at concentrations of the drug encountered therapeutically. When Michaelis-Menten kinetics were applied to data for phenytoin elimination in twenty-one adults and fifteen children, the mean apparent K_m value for the adults corresponded to a plasma drug concentration of 5·8 μg/ml, and in the children to 5·3 μg/ml. The mean V_max values in the two groups were, respectively 8·1 mg/kg per day and 12·5 mg/kg per day.     

The influence of pH on rectal absorption of sodium benzoate studied in man by rectal lumen perfusion

The influence of pH on rectal absorption of sodium benzoate in man was studied by means of a rectal lumen perfusion method and compared with in vitro measurements on diffusional transport of sodium benzoate across an octanol/water interface. For nonbuffered solutions of benzoate in vitro, it was shown that mass flux across an octanol/water interface occurs in agreement with the pH-partition model. In vivo however, mass flux increases less with decreasing pH of unbuffered perfusate than is anticipated on the basis of the pH-partition model. Probably an alkaline flow across the rectal mucosa into the lumen is present as a physiological neutralization mechanism. In contrast, buffered solutions of benzoate show a linear relationship between mass flux and decreasing pH in vitro as well as in vivo. The effect of buffer on the concentration profile of benzoic acid is qualitatively explained. It is shown that an alkaline flow across the rectal mucosa only slightly influences absorption of benzoic acid from strongly buffered solutions in the rectal lumen. It is concluded that the use of strong buffers in rectal solutions induces a drastic effect on the pH of the boundary layer, an effect not seen for unbuffered solutions. This phenomenon does not invalidate the pH-partition hypothesis but can be explained by it.     

The influence of pH on rectal absorption of sodium benzoate studied in man by rectal lumen perfusion

The influence of pH on rectal absorption of sodium benzoate in man was studied by means of a rectal lumen perfusion method and compared with in vitromeasurements on diffusional transport of sodium benzoate across an octanol/water interface. For nonbuffered solutions of benzoate in vitro,it was shown that mass flux across an octanol/water interface occurs in agreement with the pH-partition model. In vivohowever, mass flux increases less with decreasing pH of unbuffered perfusate than is anticipated on the basis of the pH-partition model. Probably an alkaline flow across the rectal mucosa into the lumen is present as a physiological neutralization mechanism. In contrast, buffered solutions of benzoate show a linear relationship between mass flux and decreasing pH in vitroas well as in vivo.The effect of buffer on the concentration profile of benzoic acid is qualitatively explained. It is shown that an alkaline flow across the rectal mucosa only slightly influences absorption of benzoic acid from strongly buffered solutions in the rectal lumen. It is concluded that the use of strong buffers in rectal solutions induces a drastic effect on the pH of the boundary layer, an effect not seen for unbuffered solutions. This phenomenon does not invalidate the pH-partition hypothesis but can be explained by it.     

Effect of suppository bases on rectal absorption rate of drugs

Thein vitro release rate andin vivo absorption rate from various suppository bases was measured for benzoic acid (soluble in lipid, moderately soluble in water) and its sodium salt (very soluble in water, insoluble in lipid). Differences in the absorption rate due to a supposed unequal spreading of the basein vivo could not be detected.Micronised fractions of sodium benzoate were absorbed at the same rate from the various bases, indicating that the transport of the particles through the bases and across the lipid-water interface, which is rate limiting in this case, is not influenced by the chemical composition of the base. Absorption of a coarse fraction of sodium benzoate was significantly faster from Witepsol H 15 and Estarinum B suppository bases than from cocoabutter and Massuppol.It is concluded that in the case of sodium benzoate an interfacial resistance between the suppository base and the rectal fluid is present. This is probably caused by a combined effect of the aggregated state of the coarse sodium benzoate particles and an elastic emulsion layer formed at the interface of cocoabutter and Massuppol, since a coarse size fraction of sodium salicylate did not show this effect.     

Pharmacokinetics of single and multiple doses of phenytoin in man

Summary Plasma concentration of phenytoin (diphenylhydantoin, DPH) have been studied in 5 volunteers after single oral and iv doses (5.0 mg sodium DPH/kg), and after multiple oral doses (2.0 mg sodium DPH/kg b.i.d. for 12 days). The data were analysed according to a one compartment model. The plasma half-life was 14.5 h±1.2 S.D. after i.v. administration, its apparent volume of distribution varied little (0.52 l/kg±0.04) and its bioavailability ranged between 0.70 and 1.0 (mean 0.87). After oral administration peak plasma concentrations were reached in 4 to 12 h. Elimination curves were slightly convex, probably due to an effect of slow absorption. Steady-state plasma levels varied twofold between individuals after multiple oral doses and exceeded those predicted from the single i.v. dose by 29 to 77%. The discrepancy was considered to be due to transition to dose-dependent kinetics.This is the last paper written in collaboration with Dr. Balzar Alexanderson before his untimely death on 2nd June 1973. We are grateful for the inspiring and fruitful experience of working with him. To honour his memory as a good friend and brilliant clinical pharmacologist a number of papers from our laboratory will be dedicated to him.     

Rate of phenytoin accumulation in man: A simulation study

Computer simulations were performed using a one-compartment open model with either first-order or zero-order input and either Michaelis-Menten or Michaelis-Menten and first-order elimination. Twelve theoretical cases constructed from various combinations of typical and atypical values for phenytoin pharmacokinetic parameters, V _max and K _m , were examined. In many cases, at least 90% of the eventual steady-state serum level would be achieved within 4 weeks when phenytoin was administered at an appropriate rate. In the case of a low-to-average V_max value and an average-to-high K_m value, an initial maintenance dose of 3–4 mg phenytoin sodium/kg/day would, within a few days, result in serum phenytoin levels above the usual therapeutic range. On the other hand, if V _max and K _m values were both low (3.8 mg/kg/day and 1.45 mg/liter, respectively), a very slow rate of accumulation would ensue. Thirty days after the start of 4 mg phenytoin sodium/kg/day, a serum level of about 16 g/ml would likely occur. The magnitude of continued accumulation beyond this level would be significantly influenced by the rate of renal elimination of unchanged phenytoin. It is recommended that, after initiation or adjustment of phenytoin therapy, serum phenytoin levels be monitored weekly for 3–4 weeks, then monthly for 2 additional months. Long-term follow-up should include serum phenytoin levels every 3– 6 months or as clinically indicated. Appreciation of the characteristics of phenytoin accumulation in relation to rate of administration and individual pharmacokinetic parameters is important for accurate interpretation of serum phenytoin levels and rational adjustment of dosage regimens.This work was supported in part by USPHS Grant AH16033.     

Gastrointestinal absorption of phenytoin from an oil-in-water microemulsion

The absorption profile of phenytoin Na emulsion were examined compared to that of phenytoin suspension after oral administration in the rat. The corn oil-in-water emulsion, particle size of 184±57.8 nm, was prepared using a microfludizer, and phenytoin Na added by shaft homogenizer. The phenytoin emulsion or suspension, 100 mg/kg, were intubated intragastrically using oral dosing needle and blood samples were withdrawn via an indwelling cannula from the conscious rat. Plasma concentrations of phenytoin were measured with HPLC using phenacetin as an internal standard. The plasma concentration versus time data were fitted to a one compartment open model and the pharmacokinetic parameters were calculated using the computer program, Boomer. The phenytoin plasma concentrations from the emulsion at each observed time were about 1.5–2 times higher than those from the suspension, significantly at time of 5, 6 and 7 hr after administration. The absorption (k_a) and elimination rate constant (k_e) were not altered significantly, however the AUC increased from 65.6 to 106.7 μg·hr/ml after phenytoin suspension or emulsion oral administration, respectively. From an equilibrium dialysis study, the diffusion rate constant (k_IE) was considerably higher from the phenytoin Na emulsion (0.0439 hr⁻¹) than phenytoin suspension (0.0014 hr⁻¹).     

Unusual absorption profile of phenytoin in a massive overdose case

The pharmacokinetics of phenytoin was evaluated in a nonepileptic adult man after the ingestion of an undetermined amount of the drug following an apparent suicide attempt. A serum phenytoin concentration of 45 micrograms/mL was observed on admission 12 hours after ingestion. Phenytoin concentrations steadily increased, reached a maximum of 114 micrograms/mL four days later, then fluctuated at about 100 micrograms/mL for a week, and slowly declined to undetectable levels within the following week. At 96.5 micrograms/mL, the unbound serum concentration was 2.5 times that observed in therapeutic drug concentrations. Computer fitting of the data indicated that the Michaelis-Menten constants, apparent volume of distribution, and renal clearance of phenytoin were consistent with those parameters reported after therapeutic doses. However, phenytoin absorption was best described by parallel first- and zero-order rate processes, with the latter proceeding for as long as two weeks following drug ingestion. This protracted absorption appears to be a result of the presence of a large concretion of phenytoin in the gastrointestinal tract, having a slow disintegration and dissolution attributable to the limited solubility of the drug in the gastrointestinal tract and to the patient's diminished intestinal motility.     

Allopurinol rectal absorption in the rabbit

Allopurinol is used clinically, with apparent success, as a rectal suppository for patients unable to take the medication by mouth. However, plasma levels of the drug or its active metabolite, oxipurinol, following administration of such dosage forms in man are either very low or undetectable. The absorption of allopurinol from rectal dosage forms was evaluated using the rabbit as a model. Following administration of the drug in suppositories formulated with cocoa butter, cocoa butter with 2% Tween 80 or polyethylene glycol, no measurable levels of either allopurinol or oxipurinol were seen. consistent with results reported in man. Administration of a rectal solution produced erratic absorption at a level less than 10% of that seen orally. The results indicate that allopurinol is not absorbed rectally and that there is no rationale for administering the drug by the rectal route. Continued clinical use of allopurinol suppositories should be documented by controlled efficacy studies.     

Intramuscular absorption of dihydroergotamine in man

In order to prevent hypotension, 1.0 mg of dihydroergotamine (Vasogin) was injected intramuscularly to 10 patients 5 minutes before spinal anaesthesia. The peak plasma concentrations were measured by a radioimmunoassay as early as at 30 minutes after drug administration, indicating a fast intramuscular absorption. According to the plasma levels the drug has to be given 15-30 minutes before spinal anaesthia.