Denji Shinkuma

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.

Correlation between dissolution rate and bioavailability of different commercial mefenamic acid capsules

A dissolution test was performed with five brands of 250 mg mefenamic acid capsule products available on the market. Three of them, the fast dissolving A and the slow dissolving D and E were subjected to a bioavailability study using a commercially available suspension as the reference. The products were administered orally in a cross-over design to 6 healthy men, and then parameters for the bioavailability were calculated from the plasma concentration-time curve. Analysis of variance indicated several significant differences among the products with respect to Cmax, Tmax and AUC. The relative availabilities of A, D and E were 86, 81 and 28%, respectively, with the AUC value (0-7 h) for the suspension as 100%. No correlation was observed between the in vitro dissolution rate of the drug from the capsules and the in vivo data, because the dispersing behavior of the capsule exerted a marked influence on its in vitro dissolution rate. To eliminate the influence of the capsule disintegrating process, a dissolution test was done on the contents of the capsules. A good correlation was found between the bioavailability and the dissolution rate of the drug from the capsule contents. Product E with the lowest bioavailability was passed through a 200-mesh sieve, placed in a new capsule, and tested for its bioavailabilky in humans. The AUC value was greater than that of the original product and the bioavailability was about equal to that of the suspension. The in vitro dissolution rate of the drug from the pulverized product E was also markedly increased.

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

Abstract— 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–∞ 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 μm 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 μm–1 min 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. The abrupt change that occurs during the weaning period is attributable not to facilitated transport but to a change in the factors regarding passive transport.

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.

Pharmacokinetic Profiles and Temporal Changes in Quantitative EEG after Imipramine Administrations

Abstract: 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 patientsexhibiting 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 theevaluation of the plasma level is adequate for the judgment.

Incompatibility of Clindamycin Palmitate Hydrochloride Dry Syrup in Internal Solutions

Incompatibility of clindamycin palmitate hydrochloride dry syrup (CLDM-P·EHCl-DS) in various internal solutions was studied. Above pH 4.1, hydrochloride was dissociated from clindamycin palmitate, and a white turbidity was produced. CLDM-P·HCl-DS was dissolved in 14 different solutions, where 10 gave a change in appearance. When stored below 5°, CLDM-P·EHCl-DS solution often turned to a white gel.