Hidenari Hirano

Distribution of ciprofloxacin into the central nervous system in rats with acute renal or hepatic failure.

Pharmacokinetic changes of various drugs have been reported in renal or hepatic failure. The present study employed ciprofloxacin, a quinolone antibiotic having neurotoxic side effects, to assess the influence of these diseases on distribution of ciprofloxacin into the central nervous system (CNS).

Quantitation of acetazolamide in rat plasma, brain tissue and cerebrospinal fluid by high-performance liquid chromatography

A simple and sensitive high-performance liquid chromatographic method for the analysis of acetazolamide (AZ) in rat blood (plasma/serum, whole blood and serum ultrafiltrate), brain tissue and cerebrospinal fluid (CSF) was described. Quantitative extraction of AZ with ethyl acetate from both buffered plasma and brain tissue homogenate (pH 8.0) was achieved. Each extract was evaporated to dryness and the residue was chromatographed on a reversed-phase column. CSF was directly analysed without extraction step. The limits of detection were 0.05 microgram ml-1 for plasma, 0.02 microgram g-1 for brain tissue and 0.004 microgram ml-1 for CSF. Calibration curves were linear over the working ranges of 0.1-100 micrograms ml-1 for plasma, 0.05-50 micrograms g-1 for brain tissue and 0.025-50 micrograms ml-1 for CSF. The reproducibility of AZ assay in the rat biologic media indicated very low relative standard deviations (RSDs). The recoveries of AZ added to plasma and brain tissue were more than 96% with an RSD of less than 5%. The present method was applied to studies of plasma concentration profiles of the drug after administration and its distribution into central nervous system.

Effects of Sho-saiko-to on the Pharmacokinetics and Pharmacodynamics of Tolbutamide in Rats

Although Sho‐saiko‐to (Xiao Chai Hu Tang), a major Chinese traditional medicine, is frequently prescribed with other synthetic or biotechnological drugs for the treatment of various chronic diseases, there is a dearth of information about interactions between sho‐saiko‐to and co‐administered drugs. This paper reports the effects of Sho‐saiko‐to on the pharmacokinetics and glucose responses of a sulphonylurea hypoglycaemic agent, tolbutamide, after their oral administration in rats.

A Chinese Traditional Medicine, Sho-Saiko-To (Xiao-Chaihu-Tang), Reduces the Bioavailability of Tolbutamide after Oral Administration in Rats

The effects of Sho-saiko-to on the pharmacokinetics of tolbutamide were investigated in rats. After intravenous administration of tolbutamide (5 mg/kg), no significant change in the pharmacokinetics of tolbutamide was observed in both groups of single and multiple (7 days) pre-administration of Sho-saiko-to (500 mg/kg). In the study of single oral administration of tolbutamide (50 mg/kg), co-administration of Sho-saiko-to tended to accelerate the initial absorption rate of tolbutamide. The area under the plasma concentration-time curve of tolbutamide after oral administration was significantly reduced by Sho-saiko-to. Subsequently, a significant decrease was observed in the oral bioavailability of this drug when Sho-saiko-to was given concomitantly. These findings suggest that Sho-saiko-to reduces the bioavailability of tolbutamide after oral administration in rats, and that this change is not related to hepatic metabolism.

Metabolic Degradation of [6]-Gingerol in Rat Jejunal Mucosa

To investigate the in vitro metabolism of [6]-gingerol, one of the major pharmacological constituents of ginger, in the intestine, [6]-gingerol was added to the jejunal mucosal and muscular tissue homogenates isolated from rats in high (50μg/ml) and low (10μg/ml) concentrations, and the residual [6]-gingerol concentration was periodically determined. In addition, the stability of [6]-gingerol at 20 μg/ml in rat whole blood was also examined in vitro to compare with the metabolic degradation in rat jejunal tissues. In the incubation mixture of rat mucosal layer with the high concentration, the residual [6]-gingerol was 96.5 ± 6.5% following 60 min of incubation. For the low that initial [6]-gingerol concentration, [6]-gingerol concentration was significantly decreased to 81.0 ± 6.1% after 60min (p < 0.001). On the other hand, cumulative amounts of [6]-gingerol decreased in jejunal mucosal homogenates with the high and low initial concentrations for 60min being 0.236 ± 0.449 and 0.231 ± 0.084μg/mg protein, respectively. The residual [6]-gingerol in the incubation mixture of muscular homogenate was about 95-98% at 60 min after the incubation in both the initial concentrations. Furthermore, no change was observed in the [6]-gingerol concentration in the incubation mixture of whole blood. These results suggest that [6]-gingerol may be subject to some metabolic degradation in the mucosal layer of rat jejunum. This first-pass metabolism in the jejunal region would be one of the reasons for the considerable amount which was not recovered as [6]-gingerol in the previous in situ absorption study.

Content Uniformity, Adhesion and Stability of Propylthiouracil Powder Prepared by Pulverizing Tablets.

Propylthiouracil (PTU), an antithyroid drug, has been widely used to treat hyperthyroidism. Since any dosage form other than tablet form is not commercially available for PTU, it is necessary to prepare the powder by pulverizing the tablet when dose adjustment is required. To clarify the efficacy of pulverizing the PTU tablet, we investigated the content uniformity, adhesiveness and long-term stability of PTU in three kinds of powders prepared with different excipients; EFC lactose, powdered lactose and potato starch.The content uniformity of PTU was excellent in all powders. In addition, there was no adhesion of PTU to two kinds of wrapping papers. On the other hand, dividing and packaging tests performed by automatic machine showed a slight effect of the excipients on PTU adhesion to the machine, specifically the lost amount of PTU after dividing and packaging was approximately 6-10% of the initial amount in all powders.PTU in these powders was almost completely stable by 90 days under the following storage conditions: R. H. 92% at 30°C, exposure to light at room temperature, and protection from light at 5°C. In addition, there was no apparent difference in the remaining percentage of PTU among these powders under each of the storage conditions. However, PTU remaining under R. H. 92% at 30°C tended to be lower than those under other storage conditions.The present findings suggest that these PTU preparations made by pulverizing tablets are applicable to practical long-term therapy use.

Study on the dissolution profile of cytochrome C in oral dosage forms.

Dissolution profiles for cytochrome c in capsule containing enteric coated granules and in enteric coated tablet were investigated. The studies were carried out by using the JP X dissolution method II (paddle method) with agitation at 100rpm in 2nd fluid of JP X disintegration test.A marked difference of dissolution profiles between two dosage forms was observed. The capsule achieved nearly 100% dissolution in 40min and the mean dissolution time (MDT) of cytochrome c in capsule was estimated as 16.6min. The tablet showed a poor dissolution profile and achieved only 72% dissolution in 40min. The MDT of cytochrome c in tablet was estimated as 22.2min. The contents of cytochrome c in capsule and tablet were determined by extraction with distilled water and phosphate buffers. Cytochrome c in capsule was completely extracted into distilled water and phosphate buffers and the content of cytochrome c in capsule was 105% of the labeled amount. A large difference between distilled water and phosphate buffers was recognized in extraction from tablet, and the content of cytochrome c in tablet was closed to the labeled amount by extraction with 1.0M phosphate buffer. The results suggest that cytochrome c may probably be adsorbed to the additives of the tablet.