Kinetics of acetaminophen after single- and multiple-dose oral administration as a gradient matrix system to healthy male subjects

The in vivo characteristics of two formulations of a recently developed controlled-release system, the Gradient Matrix System (GMS-1 and GMS-2), with acetaminophen as a model drug compound have been determined in healthy volunteers both after separate single- and multiple-dose administration. Values for the mean residence time (MRT) were increased from 5.2 h for an oral solution to 10.2 and 13.3 h for two GMS formulations after single dosing. Peak plasma concentrations were lower for the two GMS formulations after single dosing compared to the oral solution. The bioavailability, relative to the oral solution, was 91 per cent and 84 per cent for the two GMS formulations tested. After multiple dosing of one of the GMS formulations over 5 days, no change in AUC compared to the single dose AUC occurred. Steady state was reached within 2-3 days of twice daily dosing of the GMS formulation. The peak-trough-fluctuation (per cent PTF) was 44 per cent. No signs of dose dumping were observed in fasted subjects. A plateau-like plasma drug concentration profile at steady state was maintained with the GMS formulation.     

Prediction of steady state bioequivalence relationships using single dose data II-nonlinear kinetics

Two nonlinear pharmacokinetic models were simulated to investigate the relationship between single and multiple dose bioequivalency parameters for drugs such as phenytoin and propranolol which exhibit either saturable elimination kinetics or a capacity limited first pass effect. Mean Tmax, Cmax and area under the plasma-concentration time curve values from 0 to infinity (AUC 0-infinity) were compared after a single and multiple dose(s) of a test or reference drug. The aim was to determine if there were systematic changes in the limits of the single dose confidence interval at steady state that would limit the usefulness of confidence intervals following a single dose in accurately predicting bioavailability following multiple dosing. The 90 per cent confidence interval expressed as a percentage of the reference mean for Tmax, Cmax, and AUC 0-infinity showed model dependent changes from single to multiple dosing in response to the level of data error and changes in absorption. Changes in clearance also seemed to have a marked effect on the observed limits of the single and multiple dose confidence intervals especially for Cmax which showed a characteristic change in the intervals as a function of the clearance ratio. The model used to describe phenytoin had confidence intervals for Cmax and AUC 0-infinity from single to multiple dosing that were similar to that seen for the experimental data. However, the model predictions for Tmax confidence intervals following single and multiple dosing was at variance with the experimental data for formulations A and B.     

A combined single and multiple dose pharmacokinetic study of oral isosorbide-5-mononitrate in healthy volunteers.

Pharmacokinetics of 20 mg isosorbide-5-mononitrate (IS-5-MN) after single and multiple administration of two different tablet formulations were investigated in twelve healthy human subjects using an open, randomized, two-way crossover experimental design. Pentacard 20 mg tablets were compared with Ismo 20 mg tablets. After single-dose administration, both preparations caused a rapid increase in IS-5-MN plasma levels with the peak plasma concentration occurring between 0.5 and 1.5 h. For both formulations, the mean plasma half-life was found to be approximately 5 h after a single dose. In steady state during multiple dosing (t.i.d. at 8 h dosing intervals), a reduced elimination rate was observed. In line with this observation, the area under the plasma concentration-time curve (AUC) for one 8 h dosing interval during multiple dosing was higher than the extrapolated AUC after a single dose. Based on statistical evaluation of the various relevant pharmacokinetic parameters calculated from the plasma concentrations occurring after single and multiple dosing, the tablet formulations are judged to be bioequivalent.     

The bioavailability of oral nifedipine formulations: a statistical and simulation approach

The bioequivalence of three oral forms of nifedipine was assessed in a triple crossover study on 12 healthy volunteers. Single 10 mg dose was given and ten blood samples were drawn during the first 8 h after administration. Highly sensitive gas chromatographic method was used for the nifedipine assay. Pharmacokinetic parameters which describe bioavailability and general kinetic behaviour of the drug (AUC, Cmax, tmax, beta, MRT) were calculated from individual plasma profiles. They were subjected to statistical analysis (paired t-test, Hauck's inverted t-test, and Westlake's method of confidence intervals). Analogue-hybrid simulation and identification was used to generate plasma profiles of nifedipine after single and multiple dosing. Averaged plasma concentrations were used for this purpose. The three formulations studied were bioequivalent in terms of the rate of absorption. The simulation proved to be an efficient tool to substitute in vivo multiple dosing studies for assessment of bioavailability. The specific statistical methods should be preferred in bioequivalence data evaluation due to their greater power and inclusion of extraneous bioequivalence limits interval. Despite the differences among the formulations studied, each one of them should be viewed according to its intended clinical use.     

Blood levels following multiple oral dosing of chlorpheniramine conventional and controlled release preparations

An examination of steady-state performance of chlorpheniramine conventional versus controlled release products was conducted using 15 male subjects in a 3-way crossover study with a 2-week washout period between studies. The study was designed to determine if chlorpheniramine formulations provide consistent pharmacokinetic performance between individual units upon going from single dose to multiple dose therapy. In addition, the validity of predicting steady-state levels for these kinds of products using only single oral dose data was examined. The dosage forms evaluated were a conventional 4mg tablet, and 8 mg barrier coated-bead capsule, and an 8 mg repeat action tablet. Multiple doses of each product were orally administered to each subject for 6 days prior to the study day to achieve steady-state levels and on the actual study day. Serum samples were collected at specific time intervals on the study day, and chlorpheniramine levels assayed by HPLC. Pharmacokinetic analysis was based on a two-compartment open model. The mean plasma elimination half-lives of the various dosage forms were in the range 24.5–25.4h. There was no rapid release of drug from the controlled release products nor did they have drug release problems during the dosing interval. Good agreement was obtained between predicted average drug concentration at steady-state and drug concentration actually present for all the formulations studied. Based upon comparative examination of AUC, C_max, and fraction of dose absorbed data, the controlled release products administered every 12h were comparable in performance to a conventional release tablet administered every 6 h. Since the half-life of chlorpheniramine is approximately 1 day, therapeutic management may possibly be gained with dosing the patient once daily with a controlled release product or twice daily with a conventional tablet.     

Pharmacokinetics and pharmacodynamics of two formulations of verapamil.

The pharmacokinetics and pharmacodynamics of sustained release verapamil were compared with the conventional formulation in 10 healthy adult volunteers after single and multiple dosing. The mean time of maximum plasma concentrations of verapamil were significantly prolonged and the absorption rate constants significantly reduced after sustained release verapamil on both day 1 and day 10. On day 10 there was no significant difference between formulations in the relative bioavailability of verapamil. However, the area under the plasma concentration-time curve and maximum concentration (Cmax) for both formulations increased significantly with repeat dosing. On day 10, the difference in Cmax between formulations was significant. The day 10 mean peak/trough plasma verapamil concentration ratio was significantly less following the sustained release dose form. The mean PR interval was significantly prolonged by both formulations on day 1 and day 10. There were no differences between formulations other than a significantly longer PR interval following the conventional formulation 2 h after dosing on day 10.     

Extended-release formulations for the treatment of epilepsy

This review analyses the concept of extended-release (ER) formulations in epilepsy and evaluates ER formulations of carbamazepine, valproic acid and a modified-release (MR) formulation of oxcarbazepine. ER formulations are usually designed to reduce dose frequency and maintain relatively constant or flat plasma drug concentration. It is questionable whether flat plasma concentrations of an antiepileptic drug (AED) improve antiepileptic efficacy compared with fluctuating plasma concentrations. More certainly, they minimise concentration-related adverse effects, and the dosing flexibility and consistency of plasma concentrations may simplify the management of antiepileptic drug therapy. Neurologists would like ER formulations that can be administered once- and/or twice-daily to tailor therapy for the individual patient; however, switching dosage schedules from multiple dosages per day to once daily, although more convenient, will not generally improve therapeutic coverage (maintenance of effective drug concentration in biological fluids and tissue). Pharmacokinetically, the impact of a missed dose is greater the larger the dose and the less frequent the administration. Therefore, the risk of breakthrough seizure is higher during AED once-daily administration than twice-daily administration. Consequently, the increased compliance observed with fewer dosages per day should be weighed against the impact or forgiveness of omitted dose(s) and the shorter 'forgiveness' period associated with once-daily administration. Currently, the trend is to treat patients with epilepsy with ER formulations because of the better compliance, convenience and flat plasma concentration versus time curve. Thus, it seems that the term 'flatter is better' for AED plasma profiles has precipitated in the last 10-15 years among neurologists and epilepsy caregivers, and is being promoted by marketing forces of pharmaceutical companies. Data from the literature support the trend to treat epileptic patients with twice-daily administration of the existing ER formulations of valproic acid and carbamazepine, and oxcarbazepine-MR; however, the author of this article is not convinced that these ER formulations can guarantee a complete therapeutic coverage throughout the 24-hour dosing interval following once-daily administration.Epilepsy is a single-episode disease, and the convenience and possible better compliance associated with once-daily administration must be weighed against the shorter 'forgiveness' period and possible higher risk of breakthrough seizure due to sub-therapeutic plasma levels and/or omitted doses. Data suggest just a small difference in compliance between once- and twice-daily administration, with no significant difference in efficacy. Therefore, the increased compliance following once-daily administration may be counter-productive in minimising the occurrence of sub-therapeutic drug concentrations. Weighing up the advantages and disadvantages for once- versus twice-daily administration of ER formulations in epilepsy leads to a conclusion in favour of twice-daily administration.     

Steady-state plasma concentrations as a function of the absorption rate and dosing interval for drugs exhibiting concentration-dependent clearance: consequences for phenytoin therapy

Model-dependent relationships describing the effects of absorption rate and dosing interval on steady-state phenytoin plasma concentrations are presented and discussed. Utilizing a range of operative Michaelis-Menten parameters that characterize phenytoin elimination via a single capacity-limited pathway, a situation assuming instantaneous absorption (case I) is compared with the situation in which continuous constant-rate absorption occurs (case II). The results of these comparisons demonstrate that average steady-state concentrations do not differ significantly between the two cases. Ratios (case I/case II) of areas under the curve during a steady-state dosing interval substantially deviating from unity are associated with high plasma clearances and clinically low phenytoin concentrations. When the same daily dose is maintained, but the dosing interval is altered (0.25, 0.33, 0.50, 1.0 day), little difference in the average steady-state levels is observed even when absorption is instantaneous. Differences between steady-state maximum and minimum concentrations increase with prolonged dosing intervals as well as faster absorbed phenytoin formulations, but for most patients these fluctuations are therapeutically insignificant. A dimensionless parameter, Q, which is a function of the individual patient's parameters and the dosing regimen, is introduced, and its relationship with steady-state phenytoin concentrations is discussed. Formulation-related differences in phenytoin dissolution rates that may result in significantly altered absorption rates should not affect average steady-state levels unless the extent of absorption is altered. More frequent dosing is not necessary to avoid increases in the average steady-state levels when rapidly absorbed phenytoin products are administered, but may be desirable if the required daily dose is high or the individual patient exhibits a narrow therapeutic range for this drug.     

Pharmacokinetic studies with atenolol in the dog

The pharmacokinetics of the cardioselective β-adrenoreceptor blocking agent atenolol have been determined following intravenous and oral dosing to the dog. After intravenous administration at 200 mg the blood levels of parent drug were found to decay tri-exponentially with a final elimination phase half-life of about 4–5 h. The volume of distribution for the central compartment was 40 per cent body weight and the whole body volume of distribution was 160 per cent body weight. The percentage urinary recovery of parent drug was 83 per cent. Following oral dosing at 400 mg (as a solution and as a clinical trial tablet) the percentage urinary recovery was 65 per cent and the half-life extended slightly to between 5 and 6h. The peak blood levels were however very similar for the two formulations (17 and 15μg/ml for the solution and tablet respectively) and occurred at the same time (l–2h after dosing). The total areas under the blood concentration time curves were similar and the values (100 and 104ugml^?1h respectively) agreed well with that anticipated on the basis of the intravenous data. It was concluded that the two formulations were bioequivalent and that following oral dosing atenolol was almost completely absorbed with little metabolism or biliary excretion. Following chronic oral dosing at 50, 100, and 200mg/kg/day the systemic blood levels were found to increase with dose at all time points throughout the study. There was no sex or dose dependency of the half-life and its value on chronic dosing was very similar to that on acute dosing. The dose dependency of the area under the blood concentration time curves was reflected in the plateau blood levels and there was very good agreement between the experimental values and the theoretical relationship based on the acute pharmacokinetic data. In accordance with the half-life there was no accumulation at any of the dose levels studied. Thus it can be concluded that atenolol obeys linear pharmacokinetics over the dose range studied.     

Metabolic studies of synthetic isojuripidine in the dog and rat

Synthetic isojuripidine, an alkaloid of “Solanum Paniculatum”, was labelled with ³H by Wilzbach's method. In the dog, after single and repeated oral doses, the plasma levels were proportional to the amount administered and the drug seemed to be excreted very slowly. In the rat, after a single oral dose, the tritiated compound was absorbed and then retained by various tissues a long time, less than 1 per cent being eliminated in the urine in a 32 hr period. Over the same interval faecal excretion reached about 55 per cent of the dose. The metabolic pattern was studied at different times after dosing in the plasma of the two species and in the rat liver after lipophilic extraction. The major metabolite was the N-acetyl-derivative in both species. Contrary to what usually occurs, all these metabolites show less polarity than the original drug and this might explain their very slow disappearance from plasma and tissues.     

Dual effect of valproic acid on the pharmacokinetics of phenytoin

To evaluate the effects of valproic acid on the disposition of phenytoin, a single dose of 600 mg valproic acid and multiple doses of valproic acid (200 mg four times a day for 5 days) were administered together with a single oral dose of 600 mg phenytoin to 12 young male volunteers. Fraction of unbound phenytoin and the area under curve (AUC) of the total and unbound phenytoin in plasma were compared with the control phase in which only 600 mg phenytoin was given. Valproic acid increased the unbound fraction of phenytoin in both single- and multiple-dose studies by 15 per cent and 41 per cent, respectively. Single-dose valproic acid increased the total AUC of phenytoin by 11 per cent. Multiple-dose valproic acid decreased the total AUC by 7 per cent. Single-and multiple-dose valproic acid increased the unbound AUC by 25 per cent and 18 per cent, respectively, probably due to the inhibition on the metabolizing enzymes. We concluded that there are at least two mechanisms involved in valproic acid-phenytoin interaction. Whereas valproic acid displacing phenytoin on the plasma protein decreased the total drug concentration of phenytoin, the enzyme inhibition by valproic acid increased both the total and unbound concentration of phenytoin. The two conflicting mechanisms may result in different effects on the total plasma concentration of phenytoin. Therapeutic drug monitoring based on the total concentration of phenytoin may be misleading when valproic acid is co-administered.     

Absorption and disposition of fluvastatin, an inhibitor of HMG-CoA reductase, in the rabbit.

The absorption and disposition of fluvastatin have been studied in the female rabbit. In naive rabbits receiving a single oral dose (1 mg kg-1) of [3H] fluvastatin, absorption was rapid and amounted to c. 90 per cent compared with an intravenous reference dose. The drug was subject to considerable first-pass effect, its absolute bioavailability being 46 per cent. The steady-state volume of distribution of fluvastatin was 0.29 +/- 0.04 l kg-1 while the total body clearance was 0.33 +/- 0.05 1 h-1 kg-1. The administered radioactivity was excreted predominantly in feces, with the renal pathway accounting for 28 +/- 4 per cent of the oral dose and 32 +/- 3 per cent of the intravenous dose. In pregnant rabbits on a multiple oral dosing regimen, 1 mg kg-1 day-1 beginning day 6 post-conception (p.c.), steady-state concentrations in maternal blood and tissues were achieved within 5 days. The concentrations in the reproductive organs were c. 25-50 per cent of that in maternal blood while those in the kidneys and liver were considerably higher. In contrast, radioactivity levels in the fetuses and amniotic fluid decreased significantly during repeated drug administration. The fetus: placenta and amniotic fluid: placenta concentration ratios declined from 0.92 and 0.97, respectively, on day 10 p.c. to 0.10 and 0.04, respectively, on day 18 p.c., indicating a limited transfer of fluvastatin and/or its metabolite(s) across the placenta at the later stage of pregnancy. After cessation of dosing, radioactivity levels in all tissues and fluids showed a progressive and nearly parallel decline, suggesting no tissue retention of the drug.     

Pharmacokinetics and bioavailability of ergoloid mesylates

The pharmacokinetics and bioavailability of ergoloid mesylates following single administrations of various dose levels (3-9 mg), dosage forms (oral swallow and sublingual tablets, solution) and under different dosing conditions (fasted, with meal) were studied in young healthy volunteers. Male and female subjects showed a similar rate and extent of bioavailable ergoloid after drug treatment. The absorption of ergoloid using either the tablet dosage forms or the drug administered as a solution was rapid, with peak levels of about 60-80 pg ml-1 mg-1 dose achieved after 0.6 to 1.3 h. The elimination half-life for ergoloid in plasma was 2-5 h. Administration of drug with food had no effect on the extent of absorption (AUC) but lowered the absorption rate. This resulted in a reduction of (by 25 per cent) and delay in (by 1 h) achieving peak levels (Cmax). Increasing the ergoloid dose caused a proportional increase in the AUC, but a smaller than proportional increase for Cmax. The tablet formulations provided similar AUCs as the solution; the objective of the sublingual tablet formulation to provide improved bioavailability over the swallow tablet via circumvention of first-pass metabolism was therefore not realized. Transient decreases in blood pressure after ergoloid treatment paralleled the plasma level profiles. Higher ergoloid levels were paired with the larger pressure decreases.     

Saturable first-pass kinetics of propranolol

Reduced bioavailability (F) due to hepatic first-pass extraction of an oral dose (D) is a well-known pharmacokinetic phenomenon. An integrated solution for Michaelis-Menten kinetics of the first-pass effect is derived from the maximal metabolic rate (Vm), volume of distribution (Vd), first order absorption rate constant (ka), Michaelis constant (Km), and liver blood flow (Q). F = 1 - VmVd/kaD ln (1 + kaD/QKm) This equation for single dosage can also be extended to steady state kinetics after multiple dosing in which the amount of a drug present in the hepatic circulation is considered. According to the literature, the bioavailability of a single 80 mg oral dose of propranolol (F = 0.22) increases after multiple doses Fss = 0.36). Based on the first pass equations for single dosage and multiple dosing, the maximal metabolic rate (Vm = 0.043 mg l-1 h-1) corresponding to 310 mg per day and the Michaelis constant (Km = 0.10 mg/l) were calculated for propranolol. Incorporation of nonlinear plasma protein binding in this concept may explain the lack of threshold phenomenon for a single dose of less than 40 mg propranolol. Zero order absorption kinetics could explain why cumulation kinetics seem linear even at an excessive dosage of 960 mg propranolol per day. From these derivations it may be concluded that multiple dosing, increase in plasma protein binding, high absorption rate, and increased portal venous blood flow will increase bioavailability, whereas slow release formulations, fractional drug dosage, and saturable absorption kinetics will decrease bioavailability of first-pass drugs like propranolol.     

A single and multiple dose pharmacokinetic and pharmacodynamic comparison of conventional and slow-release metoprolol

Summary Pharmacokinetic and pharmacodynamic profiles for metoprolol have been measured in six healthy volunteers after single and multiple dosing with 100 mg conventional formulation twice daily and 200 mg slow-release formulation once daily. Both multidose regimes produced measurable predosing plasma concentrations of metoprolol. The plasma concentrations on the eighth day were greater than predicted by the single-dose data as indicated by the comparison of the total areas under the curve for the single dose and the dosage interval areas during multiple dosing. This increase may be associated with a change in the bioavailability and/or clearance of the drug and is currently being investigated. The peak concentrations for the two regimens were comparable but the times to peak with the slow-release regimen were significantly delayed. Both regimes produced significant beta-blocking effects over 24 h during multiple dosing, the reductions in exercise heart rate at 0 and 24 h on the eighth day corresponding to more than 20% of the maximum effect. Resting pulse rates and blood pressures were affected to a similar extent by the two regimens but neither significantly altered respiratory peak flow rates. The effects during multiple dosing were generally greater than those after a single dose and appeared to follow a more consistent trend. This observation, together with those for the plasma level data on the eighth day, illustrate the importance of performing multiple-dose studies in assessing beta-blocking drugs.     

Pharmacokinetics of Mirtazapine from Orally Administered Tablets: Influence of Gender,Age and Treatment Regimen

The effect of gender, age and treatment regimen (single dosing or chronic dosing for 7 days) on the pharmacokinetic profile of mirtazapine was studied in four groups of volunteers. The groups consisted of 9 male adults (25–43 years of age), nine female adults (25–48 years), eight elderly males (65–74 years) and eight elderly females (65–74 years), who received daily oral doses of 20 mg of mirtazapine in the form of tablets. In all groups, chronic dosing resulted in approximately 10 per cent higher plasma levels at steady state than those predicted from the single-dose kinetic profile. Although statistically significant, this effect of treatment regimen was so small that it is considered as clinically inconsequential. Mirtazapine plasma levels in adult males were approximately 50 per cent of the overall mean of the combined other groups, after both single and multiple dosing. As a consequence, statistically significant effects of gender and of age were observed. However, these differences were not large enough to justify any dose adjustments.     

Prediction of steady-state bioequivalence relationships using single dose data I-linear kinetics

Simulated data using a linear one- and two-compartment body model with different absorption characteristics were used to evaluate the ability of single dose bioavailability data to predict the relationships that exist at steady state. This was done by comparing the confidence intervals obtained from single and multiple dose data sets for the parameters of Tmax, Cmax, and area under the curve from time zero to infinity (AUC0-infinity). As a consequence of Tmax and Cmax decreasing and increasing from single to multiple dosing regimens, the confidence intervals for these parameters reflected these changes. The 90 per cent confidence interval expressed as a percentage of the reference mean increased or decreased for Tmax dependent upon the ratio of Ka test/Ka reference, and decreased for Cmax while the interval for AUC0-infinity exhibited no predictable pattern and appeared to be influenced by the amount of error in the data set. Alteration of either the dosing interval or the fraction absorbed did not affect the pattern of change in the confidence intervals for Tmax and Cmax, but the latter did result in a decrease in the interval for AUC0-infinity. Analysis of the confidence intervals for Tmax, Cmax and AUC0-infinity in bioequivalency studies for quinidine gluconate and procainamide hydrochloride following administration of single and multiple doses to different subjects appeared to be consistent with the patterns observed for the simulated data sets.     

Suppression by the spironolactone metabolite canrenone of plasma testosterone in man

Summary Healthy male subjects were given orally a single dose of 5 mg canrenone per kg body weight. Canrenone caused a significant decrease in plasma testosterone concentration already 3 hrs after administration of the drug. Suppression of plasma testosterone concentration by 50 to 60 per cent persisted over 9 hrs.It is concluded that suppression of testosterone production is an important factor in the antiandrogenic activity of spirolactones in man.     

Effervescent and standard formulations of ranitidine—a comparison of their pharmacokinetics and pharmacology

Background : An effervescent formulation of ranitidine may be absorbed faster and achieve a faster onset of action than conventional tablet form. The aim of this study was to compare the effects of effervescent formulations of ranitidine with equivalent dose standard tablets, in terms of intragastric pH and plasma pharmacokinetics in the initial 6 h following dosing.
Methods : Fifteen fasting healthy males, aged 18–31 (mean 29) years, were each randomly given, at weekly intervals, 150 mg standard and effervescent ranitidine and 300 mg standard and effervescent ranitidine. Ambulatory gastric pH was performed and plasma drug levels measured at regular intervals.
Results : Plasma ranitidine levels increased more rapidly with both effervescent formulations compared with standard tablets as indicated by mean area under curve (AUC) at 1 h ( P <0.001). However, the pH profiles produced by all four treatments were similar with a steep rise in pH at 40–60 min to give a sustained level of pH 7 for the following 5 h. The effervescent formulations produced a transient rise in pH immediately following dosing, and for 300 mg this rise was significantly different at 10–20 min compared with the standard tablet (median pH 4.75 vs. 2.3, P <0.05).
Conclusions : Plasma drug levels increase more rapidly following effervescent ranitidine. Effervescent and standard formulations of 150 and 300 mg are all equally effective in producing gastric pH 7 after 1 h. However, effervescent formulations produce an early transient rise in pH which may be of clinical benefit.     

Steady-state plasma concentrations as a function of the absorption rate and dosing interval for drugs exhibiting concentration-dependent clearance: Consequences for phenytoin therapy

Model-dependent relationships describing the effects of absorption rate and dosing interval on steady-state phenytoin plasma concentrations are presented and discussed. Utilizing a range of operative Michaelis-Menten parameters that characterize phenytoin elimination via a single capacity-limited pathway, a situation assuming instantaneous absorption (case I) is compared with the situation in which continuous constant-rate absorption occurs (case II). The results of these comparisons demonstrate that average steady-state concentrations do not differ significantly between the two cases. Ratios (case I/case II) of areas under the curve during a steady-state dosing interval substantially deviating from unity are associated with high plasma clearances and clinically low phenytoin concentrations. When the same daily dose is maintained, but the dosing interval is altered (0.25, 0.33, 0.50, 1.0 day), little difference in the average steady-state levels is observed even when absorption is instantaneous. Differences between steady-state maximum and minimum concentrations increase with prolonged dosing intervals as well as faster absorbed phenytoin formulations, but for most patients these fluctuations are therapeutically insignificant. A dimensionless parameter, Q,which is a function of the individual patient's parameters and the dosing regimen, is introduced, and its relationship with steady-state phenytoin concentrations is discussed. Formulation-related differences in phenytoin dissolution rates that may result in significantly altered absorption rates should not affect average steady-state levels unless the extent of absorption is altered. More frequent dosing is not necessary to avoid increases in the average steady-state levels when rapidly absorbed phenytoin products are administered, but may be desirable if the required daily dose is high or the individual patient exhibits a narrow therapeutic range for this drug.This work was supported in part by NINCDS Contract No. N01-NS-5-2327.