Intra- and interindividual variation in the pharmacokinetics of tacrolimus (FK506) in kidney transplant recipients--importance of trough level as a practical indicator.

BACKGROUND: Tacrolimus (FK506) is currently used as the primary immunosuppressant in clinical kidney transplantation in some centers. The purpose of this study was to evaluate the pharmacokinetics of this drug and to see if trough level, which has been used widely in therapeutic drug monitoring, can be used as an appropriate substitute for other pharmacokinetic measurement tests. METHODS: The blood concentration-time curve was studied in 10 kidney transplant recipients on 26 occasions after oral dosage of 2 to 18 mg every 12 hours. Whole blood concentration was measured by two-step immunoabsorption assay. Methylprednisolone was used as a concomitant immunosuppressive drug. RESULTS: The blood concentration-time curves showed remarkable interindividual variation. Intraindividual variation was also found, but the degree of variation was slight compared with interindividual variation. On 17 occasions of measurement in one patient, the dose was significantly correlated with trough (r = 0.684), Cmax (r = 0.838) and AUC0-12 (r = 0.817). In nine patients on nine occasions, however, the dose was not significantly correlated with trough (r = 0.351), Cmax (r = 0.270) or AUC0-12 (r = 0.355). tmax ranged from one to four hours (mean + SD; 2.8 + 1.3) and fluctuated in both intra- and interindividual measurements. In spite of a wide variation in the blood concentration-time-curve patterns, a highly significant linear relationship between trough and Cmax or AUC0-12 was observed in both intraindividual (Cmax, r = 0.876; AUC0-12, r = 0.926) and interindividual (Cmax, r = 0.943; AUC0-12, r = 0.984) measurements. CONCLUSIONS: We conclude that trough level is a practical acceptable indicator of the blood levels of tacrolimus, and can be used to monitor blood concentration.

Effect of a high-fat meal on the bioavailability of phenytoin in a commercial powder with a large particle size.

The effect of a high-fat meal on the bioavailability of free acid phenytoin (DPH) from Hydantol powder with a large particle size (mean particle size, 190 microns) was investigated in four healthy male subjects. The drug was administered as a single oral 5 mg/kg dose of free acid DPH in the fasting state, with a low-fat meal, or with a high-fat meal using a crossover study design. Seven blood samples were collected over a 34-h period following drug administration, and the drug plasma concentrations were determined by GLC. In comparison with the fasting state results, the mean area under the plasma concentration-time curve up to infinity after administration (AUC0-infinity) and the peak plasma concentration (Cmax) of DPH from Hydantol powder significantly increased about 2-fold with the intake of the high-fat meal and about 1.5-fold with the intake of the low-fat meal. The elimination rate constant was not significantly different among the three treatments. The increased bioavailability with the high-fat meal probably resulted from accelerated dissolution of the poorly soluble Hydantol powder due to the stimulation of bile flow or delay of the gastric emptying time caused by the fat intake.

Effects of food intake on the bioavailability of sulpiride from AEA film-coated tablet having a pH-dependent dissolution characteristic in normal or drug-induced achlorhydric subjects.

The effect of food intake on the bioavailability of sulpiride from a commercial film-coated tablet (100 mg/T) treated with polyvinylacetal diethylaminoacetate (AEA), which remains undissolved at pH above 4 approximately 5, were investigated in four healthy male subjects in the normal state or in a drug-induced achlorhydric state. The drug was administered as a single oral 100 mg dose of sulpiride under the fasting and nonfasting state using a crossover study design. Fifteen urine samples were collected over a 48 h period following sulpiride administration to determine sulpiride concentrations by HPLC. The bioavailability was estimated from the cumulative amount excreted unchanged in urine over 48 h (Du48). When AEA film-coated tablet was taken by subjects in the normal state, the bioavailability under the fasting state differed markedly among the four subjects due to differences in gastric acidity. The effect of food intake on the bioavailability also differed markedly among the individuals, being lower in high gastric acidity subject and higher in those with low gastric acidity subjects. When AEA film-coated tablet was taken by subjects in a simulated achlorhydric state, the bioavailability under the fasting state was very poor for all four subjects and did not show inter-subject variation. With food intake, the bioavailability increased 6-fold, probably due to the more vigorous movement of the formulation in the gastrointestinal tract, since both the basal and the meal-stimulated gastric acid secretion were markedly inhibited in the simulated achlorhydric state.

Effect of age on the gastrointestinal absorption of acyclovir in rats.

Drug elimination from the body after intravenous administration of acyclovir (20 mg kg-1) was delayed in 1-week-old rats but the pharmacokinetic data for 2.5-week-old rats were the same as those for 8-week-old rats. The areas under the plasma concentration-time curves at 0-infinity h (AUC) after oral administration of acyclovir (20 mg kg-1) decreased with increasing age. The absolute bioavailabilities for 1-, 2.5-, 3- and 8-week-old rats were 77.59, 51.52, 14.61 and 7.30%, respectively. The gastrointestinal absorption of poorly absorbed acyclovir was good for rats younger than 2.5 weeks but dropped abruptly between 2.5 and 3 weeks of age. The intestinal membrane permeability of acyclovir was studied using the everted sac method. The rate of transfer of an initial concentration of 10 microM acyclovir from the mucosal to the serosal side was constant until 60 min in rats of different ages while the rate in 2.5-week-old rats was significantly greater than that in 3-, 4- and 8-week-old rats. Abrupt in-vivo and in-vitro changes were observed in the experimental results between 2.5- and 3-week-old rats; this period coincided with the weaning period of the rat. The membrane transport mechanism of acyclovir in 2.5- and 8-week-old rats was also studied. Cumulative transferred amounts of acyclovir were linear (r = 0.99) over the range 5 microM-1 mM and dose-independent. The influence of metabolic inhibitors (sodium azide, 2,4-dinitrophenol, ouabain), purine and pyrimidine analogues (2-deoxyguanosine, guanine, adenine, uridine) and temperature on the permeation of acyclovir was studied. The permeation of acyclovir was inhibited only by 2-deoxyguanosine and guanine in 2.5-week-old rats. These results suggest that throughout the maturation period, the gastrointestinal absorption mechanism of acyclovir is predominantly via passive diffusion with little or no active or facilitated transport.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of food intake and meal size on the bioavailability of sulpiride in two dosage forms.

This study examined the influences of food intake on sulpiride (100 mg) bioavailability from a commercial film-coated tablet and of the meal size (small, medium or large) on sulpiride bioavailability from an aqueous solution in three healthy male volunteers. The cumulative urinary excretions of sulpiride for 48 h (Du48) from two dosage forms following oral administration were decreased approximately 30% by food intake. Also, a good correlation was found between the bioavailability of sulpiride from the solution and size of meals with the same dietary components. These results suggest that food intake and meal size before dosing significantly affect the gastrointestinal absorption of sulpiride.

The bioavailability of sulpiride taken as a film-coated tablet with sodium bicarbonate, cimetidine, natural orange juice or hydrochloric acid.

The bioavailability of sulpiride taken in film-coated tablet form with sodium bicarbonate or cimetidine or with natural orange juice or diluted hydrochloric acid was studied. A commercial sulpiride film-coated tablet (100 mg/T) treated with polyvinylacetal diethylaminoacetate (AEA), which remain undissolved at pH above 4-5, was given to four healthy volunteers who had fasted overnight. The subjects were divided into two groups, those showing high and low bioavailability of sulpiride from an AEA film-coated tablet. The two high bioavailability subjects took one tablet (100 mg) with 100 ml of water (1) alone, (2) together with 1 g of sodium bicarbonate or (3) during concurrent dosing with cimetidine, 200 mg three times a day. The two low bioavailability subjects swallowed one tablet with 100 ml of (1) water, (2) natural orange juice, or (3) diluted hydrochloric acid. Urine samples were collected over a 48-h period following sulpiride administration to determine sulpiride concentrations by HPLC. The bioavailability was estimated from the cumulative amount excreted unchanged in urine over 48 h (Du48). In the high bioavailability subjects, the bioavailability of sulpiride markedly decreased with the coadministration of sodium bicarbonate or cimetidine compared to when the tablet was taken alone. In the low bioavailability subjects, the bioavailability remarkably increased with the concomitant intake of orange juice or diluted hydrochloric acid over that with only water. These results suggest that the bioavailability of sulpiride from AEA film-coated tablet is influenced by the individual's gastric acidity and by coadministered drug and drink which affect gastric acidity.

Pharmacokinetic profiles and temporal changes in quantitative EEG after imipramine administrations.

A study of the relationship between pharmacokinetic profiles and temporal changes in quantitative EEG following imipramine administrations showed that a single dose of imipramine administered by different routes decreased the alpha-power spectra of healthy subjects. The EEG changes were time-related and their latent period and duration depended not on the plasma levels, but on the pharmacokinetic parameters. These effects were produced by imipramine without the influence of its desmethylated product, desipramine. Also, both single and multiple doses after oral or intramuscular imipramine administrations to depressive patients led to two types of EEG responses, with Type 1 patients exhibiting fast improvement of their symptoms. Therefore, chronologically-recorded quantitative EEG should be useful in judging the clinical prognosis of depressive patients after the imipramine treatment. At a steady state, however, neither the EEG recording nor the evaluation of the plasma level is adequate for the judgment.

Effects of food on absorption of mefenamic acid from two commercial capsules differing in bioavailability under the fasting state.

The influence of food on the bioavailability of mefenamic acid from two commercial capsules (products A and B) differing in bioavailability was studied with four healthy male volunteers. The drug was administered as a single oral dose of 250 mg under fasting and nonfasting conditions. The study used a 4 X 4 Latin-square design. Seven blood samples were collected over a 9-h period following administration and the plasma concentrations of mefenamic acid were determined by a high performance liquid chromatographical method. The bioavailability was significantly different between the two products in the fasting condition, agreeing with the result of an in vitro dissolution study. However, in the nonfasting state, the difference was not significant because the product showing poor bioavailability, product A, in the nonfasting state showed marked improvement. On the other hand, the product showing good bioavailability, product B, was not affected by food.

Bioavailability of mefenamic acid: influence of food and water intake.

The influence of food and water intake on mefenamic acid (N-2,3-xylylanthranilic acid) bioavailability from commercial capsules of high bioavailability was studied in four healthy male volunteers. The drug was administered as a single oral dose of 250 mg, under fasting or nonfasting conditions, and a 4 X 4 Latin-square design was used. Eight blood samples were collected over a 24-h period following drug administration, and the drug plasma concentrations were determined by HPLC. The bioavailability of mefenamic acid from capsules was markedly influenced in the fasting subjects by the water but not by the food intake. A good correlation was found between the bioavailability and amount of water ingested with the drug in the fasting subjects. The area under the plasma concentration-time curve (AUC0-infinity) of mefenamic acid was highest when the capsule was taken with 50 mL of water or immediately after a meal. Increasing the amount of water from 50 to 500 mL in the fasting subjects caused a significant reduction in AUC0-infinity.

Gastrointestinal absorption of sulpiride in rat.

A two-compartment model could be used to describe the elimination of sulpiride from plasma after intravenous administration of 25 and 50 mg/kg doses to rat. The absolute bioavailability after oral administration was only about 15% which was also the level after intraduodenal administration. Higher bioavailabilities were found after mesenteric venous and intravenous administration (sham-operated rat) due to a decrease in the beta-value (elimination rate constant). The low bioavailability of sulpiride following oral administration was concluded to result, not from metabolism in the liver, but from reduced absorption by the gastrointestinal tract.

Effect of benzodiazepine derivatives on amygdaloid-kindled convulsion.

An evaluation of the anticonvulsant effect of five kinds of benzodiazepine derivatives using amygdaloid-kindled rats yielded the following pharmacological properties of benzodiazepine derivatives: (1) Bromazepam, lorazepam and nitrazepam block the behavioral seizure response and also shorten the after-discharge duration simultaneously in both primary and secondary epileptogenic foci. (2) Diazepam has little effect on shortening the after-discharge duration at least in the primary epileptogenic focus though it blocks the behavioral seizure response. (3) Although clonazepam can block the behavioral seizure response and shorten the after-discharge duration, further investigations are necessary to define its efficacy.