Absolute bioavailability, rate of absorption, and dose proportionality of sulpiride in humans.

The pharmacokinetics of orally administered sulpiride was determined in a series of three studies. In the first study, 12 subjects received an oral solution (200 mg) and an iv dose (100 mg). The second study also included an iv dose, and examined the absorption of 200-, 300-, and 400-mg doses given as 50-mg capsules to six subjects. The third study compared the bioavailability of a 200-mg capsule dose with a 200-mg im dose in eight subjects. The concentration of sulpiride in plasma, red blood cells, and urine was measured by HPLC. The disposition of the drug was generally best described by a two-compartment pharmacokinetic model, with absorption appearing to occur by two sequential zero-order processes. The fraction of dose absorbed after oral administration was approximately 30% based on plasma and urine data. After the 200-mg dose, the mean elimination half-life was 7.0 h, and the mean residence time was 8.4 h. For each subject, total clearance, corrected for the fraction absorbed, and renal clearance were similar. The dose proportionality study demonstrated linear disposition kinetics.     

Absolute bioavailability and noncompartmental analysis of intravenous and intramuscular Cefotan (cefotetan) in normal volunteers

Cefotetan (1 g) was administered to 12 normal volunteers as a 30 minute intravenous infusion and as an intramuscular injection. The pharmacokinetic parameters were estimated using noncompartmental analysis. The mean +/- SD maximum plasma concentration, terminal half-life, and systemic clearance after intravenous infusion were 158 +/- 21 micrograms/mL, 4.54 +/- 1.05 hours, and 29.1 +/- 3.8 mL/min/1.73 m2, respectively. Renal clearance and nonrenal clearance accounted for 63.1% and 36.9% of the systemic clearance, respectively. The mean +/- SD maximum plasma concentration, time to maximum concentration, terminal half-life, and absolute bioavailability after intramuscular injection were 75.5 +/- 8.7 micrograms/mL, 1.33 +/- 0.48 hours, 4.32 +/- 0.77 hours, and 0.931 +/- 0.193, respectively. Moment analysis gave average +/- SD mean residence times (MRT) of 4.98 +/- 0.75 and 5.86 +/- 0.77 hours after intravenous and intramuscular administration, respectively. The average +/- SD mean absorption time (MAT) after intramuscular injection was 1.11 +/- 0.57 hours. The mean +/- SD steady-state volume of distribution after intravenous infusion was 0.129 +/- 0.024 L/kg. The mean +/- SD cumulative percentage of the dose excreted in the urine in 24 hours were 61.1 +/- 11.4% and 50.4 +/- 13.5% after intravenous and intramuscular dosing, respectively. The maximum urinary cefotetan concentrations occurred during the first 2 hours after dosing by both routes of administration. Cefotetan tautomer was detected in the plasma and urine of all subjects after both routes of administration, but the mean concentrations were only minimal compared to those for cefotetan. In conclusion, intramuscular cefotetan (1 g) is rapidly and almost completely absorbed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of ranitidine in patients with renal failure

The pharmacokinetics of ranitidine were studied in ten patients with renal failure (creatinine clearance, 6-54 mL/min) after intravenous (IV) (50 mg) and oral doses (150 mg). After oral administration, peak plasma concentrations of 378-808 ng/mL were obtained in two to six hours. Plasma concentrations declined very slowly and concentrations greater than 100 ng/mL were obtained for 16 to 20 hours after the dose. The elimination half-life following oral administration was 8.5 +/- 2.8 hours (standard deviation [SD]), and the bioavailability of ranitidine was 43.3% +/- 10.5%. After IV administration, the elimination half-life, plasma clearance, renal clearance, and volume of distribution were 7.0 +/- 1.0 hours, 170 +/- 38 mL/min, 36.0 +/- 25.0 mL/min, and 1.3 +/- 0.4 L/kg, respectively. About 20% of the IV dose and 9% of the oral dose were recovered unchanged in urine. There was a significant correlation between the renal clearance of ranitidine and creatinine clearance (r = .74, P less than .05) after IV administration. The elimination half-life in patients with renal insufficiency is about three times greater than that reported in the literature for healthy subjects. Similarly, the plasma clearance in these patients is about 20% of that reported in healthy subjects. The results indicate that ranitidine elimination is appreciably reduced in renal failure and that an adjustment of dose in patients with renal failure is warranted. A dose of 75 mg bid may be adequate in maintaining the therapeutic plasma concentrations that are required for adequate H2-blocking activity.     

Sulpiride pharmacokinetics in humans after intramuscular administration at three dose levels

Pharmacokinetics of the disinhibitory psychotropic agent sulpiride was investigated in 9 healthy male subjects after intramuscular administrations of 50, 100, and 200 mg in a 3 X 3 Latin square design. Plasma and urine concentrations were measured by HPLC for 36 and 48 h, respectively. The lowest detectable concentration was 10 ng/mL. Plasma concentration versus time and urinary excretion rate versus time curves were consistent with an open two-compartment body model, where mean +/- SD apparent half-lives of the absorption from muscle, lambda 1 distribution, and lambda 2 elimination phases were 6.96 +/- 2.64 min, 0.220 +/- 0.120 h, and 6.74 +/- 2.67 h, respectively. The initial volume of distribution was 0.145 +/- 0.063 L/kg, the steady-state volume of distribution was 0.639 +/- 0.184 L/kg, and the total clearance was 89.8 +/- 22.3 mL/min. The microscopic rate constants were k12 = 2.53 +/- 1.13 h-1, k21 = 0.674 +/- 0.197 h-1, and k10 = 0.635 +/- 0.298 h-1. Comparison of total clearance (89.8 mL/min), renal clearance (83.0 mL/min), and renal clearance of unbound drug (97.6 mL/min, f = 0.15) indicated that sulpiride is mainly excreted unchanged by the renal route, 93.1 +/- 6.6% of the administered dose being recovered unchanged in urine. Statistical evaluation of all the above parameters, determined at the three dosage levels, did not show any variations related to dose; the pharmacokinetics of sulpiride, over the dose range tested, was therefore linear and independent of dose. The two-compartment body model proposed was validated by digital computer simulation on a small digital computer (32K).     

Pharmacokinetics of oral pramiracetam in normal volunteers

The pharmacokinetics of pramiracetam, a new, investigational, cognition activator, were assessed in normal male volunteers as part of a clinical tolerance study. In a double-blind, randomized design, two groups of six subjects each received alternating placebo and single 400, 800, 1,200, and 1,600 mg oral doses of pramiracetam after an overnight fast. Mean (+/- SD) peak plasma concentrations of the four dose groups (2.71 +/- 0.54, 5.40 +/- 1.34, 6.13 +/- 0.71, 8.98 +/- 0.71 micrograms/mL) were attained between two to three hours following drug administration. The harmonic mean elimination half-life (4.5-6.5 hours), the mean total body clearance (4.45-4.85 mL/min/kg), the mean renal clearance (1.83-3.00 mL/min/kg), and the mean apparent volume of distribution (1.82-2.94 L/kg) were independent of dose, whereas the peak plasma concentrations and area under the curves increased as a linear function of dose. No significant side effects were observed at any dose level.     

Pharmacokinetics and bioavailability of a new formulation of teicoplanin following intravenous and intramuscular administration to humans.

Pharmacokinetics, bioavailability, and local tolerance (at the site of intramuscular administration) of a new formulation of teicoplanin (400 mg/3 mL) were investigated in 24 normal, healthy, male volunteers. A single dose of 6 mg/kg was administered intravenously and intramuscularly using a randomized crossover design. Volunteers and investigator were blinded as to the route of administration; placebo was administered by the other route. Blood and urine samples were collected for 21 days and were analyzed for microbiological activity. The median (range) pharmacokinetic parameters of teicoplanin following single-dose iv administration were as follows: steady-state volume of distribution of 1.6 (1.2-2.8) L/kg; total clearance of 10.2 (8.6-15.1) mL/h/kg; renal clearance of 10.0 (7.9-13.8) mL/h/kg; and terminal disposition half-life of 168 (111-278) h. Following single-dose im administration, significantly more subjects complained of pain following administration of teicoplanin (58%) compared with placebo (4%). Teicoplanin was completely absorbed with a median (range) peak serum concentration of 12.3 (6.6-37.5) micrograms/mL occurring at a median (range) time of 4.1 (0.7-6.1) h. Since the 90% confidence interval for the ratio of areas under the serum concentration-time curve falls within the range of 80 to 120%, the extent of systemic absorption of teicoplanin following im administration is equivalent to that following iv administration.     

The urinary disposition of intravenously administered 11-nor-9-carboxy-delta-9-tetrahydrocannabinol in humans

The objective of this study was to investigate the fraction of an administered dose of 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (THCCOOH) that is actually excreted into urine and to determine its urinary half-life independent of the parent compound. Ten healthy, male marijuana nonusers who were enrolled in the study were administered a single dose of 5 mg THCCOOH by the intravenous route. Urine specimens were collected up to 96 hours after administration. Samples were extracted before and after alkaline hydrolysis. The concentration of unconjugated and total THCCOOH was determined using gas chromatography-mass spectrometry. Most of the THCCOOH found in urine was conjugated, with only 0.14 +/- 0.08% of the dose present as unconjugated THCCOOH. The amount of conjugated THCCOOH ranged from 149.3 to 559.8 (mean +/- SD, 342.8 +/- 117.3) microg, representing a recovery of 3% to 11% of the administered dose. The measured amounts of total THCCOOH were low and highly varied among individuals. Renal excretion does not appear to be the preferred elimination pathway for THCCOOH. Urinary elimination half-life of unconjugated and conjugated THCCOOH ranged from 9.0 to 27.4 (mean +/- SD, 17.3 +/- 5.3) hours and from 10.7 to 27.6 (mean +/- SD, 16.0 +/- 5.0) hours, respectively. Although preliminary in nature, the actual urinary elimination half-life of THCCOOH appears to be significantly shorter than its apparent or terminal half-life reported from single or multiple dosing of delta-9-tetrahydrocannabinol (THC).     

Deuterium isotope effect on the toxicokinetics of monomethylamine in the rat

The single-dose toxicokinetics of monomethylamine has been characterized in the rat by HPLC assay of serial blood samples. Biphasic first-order elimination was observed following an iv bolus dose of 19 mumol/kg with a terminal half-life of 19.1 +/- 1.3 min (mean +/- SE, N = 4). The apparent steady state volume of distribution, systemic blood clearance, and renal blood clearance were 1.21 +/- 0.09 liter/kg, 53.4 +/- 3.5 ml/min/kg, and 5.72 +/- 0.53 ml/min/kg, respectively. The administration of an intragastric dose permitted the calculation of the systemic bioavailability of monomethylamine as 69 +/- 3%. Duplicate experiments using the structural analogue with deuterium atoms substituted for hydrogens on the methyl group revealed a much slower elimination of the compound, although ultimately, 5 times as much was excreted unchanged in the urine. Isotope effects calculated as the ratios of terminal half-life, systemic blood clearance, and systemic bioavailability were 1.9, 2.2, and 1.8, respectively.     

Pharmacokinetics of the trichothecene mycotoxin verrucarol in dogs

Verrucarol is a simple trichothecene which is structurally related to T-2 and HT-2 toxins. Several macrocyclic trichothecenes which are ester derivatives of verrucarol possess antitumor activity. The pharmacokinetics of verrucarol has been studied in eight dogs following iv and oral administrations (0.4 and 0.8 mg/kg, respectively). The iv study showed that verrucarol has a mean (+/- SD) clearance of 11 +/- 5.5 mL/min/kg, a volume of distribution of 1.2 +/- 0.6 L/kg, and a terminal half-life of 1.6 +/- 0.5 h. Following oral administration, the absolute bioavailability of verrucarol was 44 +/- 33%, and its terminal half-life was similar to that obtained after iv administration. In comparison with T-2 and HT-2 toxins, verrucarol has a longer half-life and a lower clearance, and its liver extraction ratio is about one third of that of T-2 and HT-2 toxins. Therefore, verrucarol is less susceptible to a liver first-pass effect and its partially absorbed after oral administration. These characteristics make verrucarol the first partially absorbed trichothecene whose pharmacokinetics was investigated following oral administration.     

Pharmacokinetics of sulpiride after intravenous administration in patients with impaired renal function

Single intravenous doses of sulpiride 100 mg were administered to 18 patients with renal function impairment, and 6 healthy volunteers. The plasma concentration-time profile is described by a 2-compartment open model. The differences between the pharmacokinetic parameters of sulpiride for the 2 groups were statistically significant. Elimination half-life, mean residence time and area under the plasma concentration-time curve are significantly greater in renal failure; renal and total clearance, and the cumulative amount of unchanged sulpiride in urine, are significantly reduced but volume of distribution remains unchanged. Creatinine clearance was strongly correlated with renal clearance of sulpiride, elimination rate constant, area under the curve and cumulative amount excreted in urine. For patients with impaired or physiologically reduced renal function receiving long term sulpiride treatment, a 35 to 70% reduction in dose, or extension of the dosage interval by a factor of 1.5 to 3, may be required.     

Disposition of pentopril, a new orally active angiotensin-converting enzyme inhibitor, and its active metabolite in rats

The disposition characteristics of pentopril (the ethyl ester) and its active carboxylic acid metabolite (CGS 13934) were determined in conscious rats after separate intravenous administrations of both compounds. The relationship between plasma concentration and pharmacological effect was also evaluated. The extent of apparent bioavailability of the active metabolite was determined after oral administration of pentopril. Pharmacokinetic parameters were calculated from the plasma concentration-time data for both the parent drug and its active metabolite after their separate intravenous administrations using a one-compartment model for the drug and a two-compartment model for the metabolite. The elimination half-life for the drug was approximately 1 min. The elimination half-life for the metabolite was 13 min (SD, +/- 3.5, n = 4) after its direct intravenous administration, but increased to an apparent half-life of 20 min (SD +/- 5, n = 5) when formed in vivo as a metabolite. Comparison of the formation rate of the metabolite and the elimination rate of the parent drug indicated that the parent drug was rapidly and completely hydrolyzed to the acid metabolite as soon as it reached the systemic circulation. No parent drug was detected in plasma after its oral administration. The apparent bioavailability of the acid metabolite was 66% after oral drug administration. A close relation between inhibition of pressor response to angiotensin I (AI) and plasma concentration of the active metabolite was observed when plotted against time after drug or metabolite administration. A Michaelis-Menten function correlated (multiple r2:0.995) well between effect and plasma metabolite concentration with mean concentration for 50% of maximum inhibition, IC50, of 3.6 X 10(-7) M (0.11 microgram/mL).     

Kinetics of aluminum in rats I: Dose-dependent elimination from blood after intravenous administration

Aluminum (Al) kinetics after intravenous bolus administration were studied in the rat. The animals received either 0.1 or 1.0 mg/kg (n = 6 at each dose) of elemental Al as the sulfate salt. The Al content of serial blood samples was determined by flameless atomic absorption spectrophotometry. Blood and plasma Al-time profiles after both doses were monoexponential in most cases. Increasing the administered dose increased the elimination half-life (mean +/- SD) from 1.20 +/- 0.25 to 2.41 +/- 0.26 h. A corresponding decrease in systemic clearance was observed (49.6 +/- 11.0 to 18.4 +/- 4.6 mL/kg.h). Both changes were significant (p less than 0.05). Significant differences were also observed in the volume of distribution, the values of which were 78.3 +/- 17.2 and 58.9 +/- 8.5 mL/kg at the low and high doses, respectively. At both doses, blood:plasma ratios ranged from 0.8 to 1.0, indicating considerable uptake/binding of the element by blood cells.     

Dose-dependent and time-dependent pharmacokinetics in the dog after intravenous administration of dextrorphan.

The disposition of dextrorphan after single ascending iv doses and multiple iv dosing regimens was studied in Marshall beagle dogs. A dose-dependent decrease in plasma clearance was observed after the administration of single iv doses of 0.88 mg/kg, 2.64 mg/kg, and 8.8 mg/kg of dextrorphan (i.e. mean plasma clearance values +/- SD were 100 +/- 25 vs. 68 +/- 28 vs. 48 +/- 20 ml/min.kg, respectively; p less than 0.001). Upon multiple dosing, the plasma clearance of dextrorphan increased in a time-dependent fashion for the two highest doses, approaching values observed for the 0.88 mg/kg/day iv dosing regimen. Female dogs exhibited a greater increase in plasma clearance with time. For all dogs, however, dextrorphan plasma clearance approached or exceeded hepatic plasma flow rate, suggesting the possibility of extrahepatic metabolism or elimination. Modest dose- and time-dependent changes in the steady-state volume of distribution of dextrorphan also were observed. The AUC of the conjugated metabolites of dextrorphan decreased in a time-dependent manner for the 8.8 mg/kg/day dosing regimen. The nonlinear kinetics of dextrorphan after iv administration appeared to occur only after potentially toxic dosing regimens of dextrorphan hydrochloride. We postulate mechanisms to explain the dose- and time-dependent kinetics of dextrorphan observed in the beagle dog.     

Pharmacokinetics of iohexol, a new nonionic radiocontrast agent, in humans

Sixteen healthy men received iohexol intravenously at a concentration of 346 mg of iodine/mL. Doses of 500, 750, 1000, and 1500 mg of iodine/kg of body weight were administered to four volunteers each. Neither clearance nor percent of dose excreted in the urine showed any significant correlation with size of the dose. The overall mean (+/- SD) renal and total body clearances were 120 +/- 18.6 and 131 +/- 18.6 mL/min, respectively. The overall mean apparent volume of distribution was 165 (+/- 30.7) mL/kg. Urine contained 92.3 +/- 4.4% of the dose. Most of the drug (89.9%) was excreted within the first 12 h. An open three-compartment body model gave the best fit to the experimental data. The mean apparent first-order terminal elimination (gamma-phase) half-life was 12.6 h.     

Pharmacokinetics of intravenous bepridil in patients with coronary disease

The pharmacokinetics of intravenous bepridil (1-[2-(N-benzylanilino)-1-(isobutoxymethyl)ethyl]pyrrolidine ) were studied in 16 patients undergoing cardiac catheterization for evaluation of coronary disease, all with normal base-line hemodynamic and renal functions. Ten patients received 3 mg/kg and six patients received 4 mg/kg of bepridil infused over a period of 30 min. Plasma bepridil concentrations were measured by HPLC and analyzed by model-dependent and model-independent methods. The mean (+/- SD) maximum plasma bepridil concentrations at the end of the infusion were 2047 +/- 820 ng/mL (3 mg/kg) and 2478 +/- 1426 ng/mL (4 mg/kg). Postinfusion bepridil concentrations were best described by a two-compartment open model. The model-dependent harmonic mean distribution and elimination half-lives were 1.7 h (range: 1.1-2.2 h) and 19.7 h (range: 8.0-61.9 h), respectively. The harmonic mean elimination half-life from model-independent analysis was 14.9 h (range: 7.4-64.0 h). The arithmetic means of other model-independent kinetic parameters were systemic clearance, 0.524 +/- 0.215 L X kg-1 X h-1; Vd, 15.3 +/- 10.9 L/kg; and Vdss, 10.1 +/- 6.0 L/kg. Model-dependent and model-independent estimates of half-life and clearance agreed reasonably well. Bepridil was well tolerated, effecting little or no change in central hemodynamics or EKG intervals. The extensive distribution and relatively slow clearance of bepridil account for its long elimination half-life. Intravenous bepridil appears to be a safe calcium (II) antagonist that is suitable for once-a-day dosing.     

Pharmacokinetics of 2',3'-dideoxycytidine after high-dose administration to rats.

The pharmacokinetics of 2',3'-dideoxycytidine (DDC) was characterized after iv administration of a high dose (500 mg/kg) of DDC to rats. The high dose was administered to optimally characterize plasma DDC concentration and urinary excretion rate versus time profiles. Drug concentrations in plasma and urine were determined by HPLC. Plasma DDC concentrations and DDC urinary excretion rates as a function of time were fitted simultaneously to a two-compartment model. Drug concentrations in plasma and urinary excretion rates declined in parallel with a terminal half-life of 1.29 +/- 0.07 h (mean +/- SD). Total, renal, and nonrenal clearances were 1.48 +/- 0.15, 0.73 +/- 0.38, and 0.75 +/- 0.36 L/h/kg, respectively. Renal clearance exceeds glomerular filtration rate in the rat, indicating that DDC undergoes active renal tubular secretion. The unbound secretory intrinsic clearance for DDC renal excretion was moderate, with a value of 0.4 L/h. The steady-state volume of distribution of DDC was 1.25 +/- 0.13 L/kg. Pharmacokinetic parameters after iv administration of 500 mg/kg of DDC were virtually identical to those reported previously after administration of 10-200 mg/kg of the nucleoside to rats. Thus, the disposition of DDC in the rat is independent of dose over a range of 10 to 500 mg/kg. High doses of DDC can be administered to rats to allow for complete characterization of the disposition pattern of the drug without complexities due to any nonlinearity.     

Pharmacokinetics of parenteral dezocine in rhesus monkeys and dogs

Pharmacokinetic parameters of the analgesic, dezocine, were determined after intravenous and intramuscular injection (1 mg/kg) to rhesus monkeys and dogs. In both species, the drug was rapidly distributed after intravenous administration and then eliminated with a mean half-life of 2.4 hr. Systemic clearance was 54.8 +/- 8.6(SD) and 65.8 +/- 14.0(SD) ml/min/kg in the rhesus monkey and dog, respectively. Glucuronidation was recognized as a major metabolic pathway in both species, and sulfate conjugation was indicated in the dog. Renal elimination of dezocine was minimal. Less than 4% of the dose was eliminated as unchanged dezocine in urine of rhesus monkeys and 1% of the dose in dog urine. After im administration, release from the injection site was rapid and no metabolism at the injection site was indicated. Multiple-dose experiments in dogs did not reveal accumulation. The acquisition of data was made possible by the development of a sensitive, specific assay, which depends on gas-liquid (electron capture) chromatography of a pentafluorobenzoylated derivative of dezocine.     

Pharmacokinetics of oxiracetam in patients with renal impairment after a 800 mg single oral dose

The pharmacokinetics of oxiracetam in patients with renal impairment were investigated after administration of a 800 mg single oral dose of oxiracetam. The renal insufficiency was estimated on the basis of the creatinine clearance (CLcr) which ranged from 9 to 95 ml/min among the 20 patients. In plasma, the terminal elimination half-life (T1/2) ranged from 10.6 to 68.1 h, the highest T1/2 corresponding to the patients with a high degree of renal impairment. In urine, the amounts of oxiracetam excreted during the 48 h postdosing represented 8.3 to 82.6% of the dose. They were lower in patients with a high degree of renal impairment. The correlations between the total clearance of oxiracetam, the renal clearance, the terminal apparent elimination rate constant in plasma, and CLcr were estimated by linear regression analysis. The correlation coefficients were 0.916, 0.985 and 0.803 respectively. The apparent volume of distribution of the central compartment V(1) and the total volume of distribution at the steady-state V(SS) were not dependent on the degree of renal impairment. The mean values +/- SD were 25.9 +/- 13.0 litres and 48.3 +/- 21.5 litres respectively. Oxiracetam concentrations in plasma of patients were estimated for repeated administration of 800 mg of oxiracetam.(ABSTRACT TRUNCATED AT 250 WORDS)     

Phenytoin prodrug 3-phosphoryloxymethyl phenytoin (ACC-9653): pharmacokinetics in patients following intravenous and intramuscular administration

A phenytoin prodrug, 3-phosphoryloxymethyl phenytoin (ACC-9653; 1), has been developed with more favorable physicochemical properties than phenytoin for parenteral administration. The purpose of this study was to evaluate the pharmacokinetic profile of 1 following iv and im administration in adult patients receiving chronic oral phenytoin monotherapy. Each patient (9 males, 1 female) received a single iv dose of undiluted 1 equivalent to their twice daily phenytoin dose (100-200 mg). An equivalent dose of im 1 was administered in the gluteus maximus muscle one week later. Serial blood samples were obtained after each dose. Phenytoin and 1 concentrations were measured using HPLC. Compartmental analysis using weighted nonlinear least squares, and noncompartmental pharmacokinetic analysis were performed on each patient's concentration-time data. Data following iv 1 in eight of ten patients were best described using a two-compartment model. Mean pharmacokinetic parameter estimates for iv 1 in these patients were central volume of distribution (Vdc) of 0.040 +/- 0.0084 L/kg and plasma disappearance half-life (t1/2 alpha) of 8.0 +/- 2.9 min ("conversion" t1/2). Overall mean clearance (CL) was 0.24 +/- 0.080 L/kg/h in the 10 patients. Mean pharmacokinetic parameter estimates for im 1 were a rate constant (ka) of 2.47 +/- 1.41 h-1 and an absolute bioavailability (F) of 100.5 +/- 20.3%. Mean observed tmax values for phenytoin were 0.57 +/- 0.26 and 1.46 +/- 0.76 h following iv and im 1, respectively. Model-independent estimates of clearance agreed well with the compartmental analyses. Steady-state predose phenytoin concentrations did not significantly vary from the comparable concentrations following iv 1 administration (p = 0.22).(ABSTRACT TRUNCATED AT 250 WORDS)