Yukisumi Iizuka

The Optical Resolution of Racemic Chlorpheniramine and Its Stereoselective Pharmacokinetics in Rat Plasma

Abstract— An ovomucoid‐conjugated column has been developed for the chiral stationary‐phase liquid chromatographic resolution of racemic chlorpheniramine with a quantitation limit of 0·05 μg mL−1. The assay was used to study the stereoselective kinetics of chlorpheniramine enantiomers in rats. After bolus intravenous administration of racemic chlorpheniramine maleate (20 mg kg−1), plasma concentration of the (–)‐form was higher than that of the (+)‐form. In the elimination phase, the concentrations of (+)‐ and (–)‐chlorpheniramine in the plasma declined biexponentially with half‐lives of 18·2 and 50·0 min, respectively. Although there was no significant difference in blood‐to‐plasma concentration ratio of both enantiomers, the apparent total blood clearance of (+)‐chlorpheniramine was twice as large as that of the (–)‐isomer. Binding of (–)‐chlorpheniramine to rat plasma protein was stronger than that of (+)‐chlorpheniramine suggesting stereoselective pharmacokinetics may be due to a difference in the plasma protein binding.

The disposition of thioperamide, a histamine H3-receptor antagonist, in rats

Abstract— An HPLC method using an ovomucoid‐conjugated column has been developed for measurement of thioperamide, a histamine H3 antagonist, with a minimum quantitation limit of 0·05 μg mL−1 The assay was used to study the disposition of thioperamide in rats. After bolus intravenous administration of thioperamide (10 mg kg−1), the plasma concentration decreased monoexponentially with a half‐life of 26·9 min. The apparent total body clearance of thioperamide from rat plasma was 74·6 mL min−1 kg−1. Although thioperamide was quickly transferred to various tissues, its concentrations in peripheral tissues were higher than that in the brain. However, the brain regional tissue/plasma ratios of thioperamide increased continuously after its injection.

In vivo microdialysis measurement of histamine in rat blood effects of compound 48/80 and histamine receptor antagonists

An in vivo microdialysis method combined with a highly sensitive HPLC method which was developed for the analysis of the mediators in the CNS has been applied to assay histamine concentrations in the blood. The technique was used to study the effects of compound 48/80 and histamine receptor antagonists on histamine release in the blood of rats. The mean basal level of histamine in the blood measured by in vivo microdialysis was 177.8 +/- 11.1 pmol/mL. This level was not affected significantly by intraperitoneal (i.p.) injection of saline, and remained at the constant level for at least 8 hr after injection of saline. After i.p. injection of histamine (0.5 mg/kg), histamine was quickly detected in the blood of the jugular vein. Moreover, because the recovered histamine in the dialysate is directly proportional to the free fraction in the blood, the in vivo microdialysis method of blood is a reliable method of examining histamine release into the blood. In our experiments, the histamine level in dialysates from rat jugular vein was markedly increased by compound 48/80 (2.0 mg/kg, i.p.), demonstrating the histamine release into the blood from mast cells. However, there was no increase in histamine concentration after an i.p. injection of histamine receptor antagonists, such as pyrilamine (2.0 mg/kg), d-chlorpheniramine (2.0 mg/kg), cimetidine (10 mg/kg), or thioperamide (10 mg/kg). Thus, the present results suggested that these histamine receptor antagonists might not have an influence on histamine release into the blood.

Enantioselective Pharmacokinetics of α‐Fluoromethylhistidine in Rats and Its Comparison with Histidine

Abstract— The enantiomer‐specific pharmacokinetics of histidine and its analogue, α‐fluoromethylhistidine (FMH), were investigated in rats. After bolus intravenous administration of each enantiomer of histidine or FMH at a dose of 40·3 mg kg−1 as free base equivalents, the plasma concentrations of l‐histidine, d‐histidine, (S)‐FMH and (R)‐FMH decreased biexponentially with half‐lives of 39·2, 20·8, 32·8 and 25·0 min, respectively, in the elimination phase. Although the concentration of l‐histidine in the plasma was lower than that of d‐histidine, there was no large difference in plasma concentration‐time curves of the enantiomers of FMH. The apparent total clearance of l‐histidine from rat plasma was about 4 times that of d‐histidine or the enantiomers of FMH. l‐Histidine was quickly transferred to the peripheral tissues where the concentrations also decrease biphasically. l‐Histidine penetrated more rapidly into the brain than either its d‐enantiomer or a compound closely related in structure such as FMH. However, the disappearance of l‐histidine from the various brain regions was very rapid. In contrast, brain/plasma ratios of d‐histidine and (S)‐FMH increased continuously after injection of these compounds, indicating that d‐histidine or (S)‐FMH partitioned into the brain and was very slowly removed from the brain; (R)‐FMH was not distributed to the brain. These results suggested stereoselectivity in disposition of histidine and FMH enantiomers in rats.

Diarrhea and Biogenic Amines : Regional Changes in Brain Histamine Concentration and Serotonin Metabolism Following Castor Oil-Induced Diarrhea in Rats

Regional changes in concentrations of histamine (HA), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in the rat brain were investigated after diarrhea induced by castor oil. Significant decreases in body weight were observed from the 3rd day after daily oral administration of castor oil (2.5 ml/kg). HA concentrations in most brain regions decreased in diarrhea induced by a single administration of castor oil. A significant decrease was recognized particularly in the case of the hippocampus. The influence has begun to appear in the thalamus and hypothalamus in consecutive (3 d) administration. HA concentration in the striatal and hypothalamic regions of the rat treated with castor oil for 9 d significantly decreased in comparison with the control group. On the other hand, an inhibition of 5-HT turnover was observed in the thalamus at 3 h after a single administration of castor oil. However, this inhibition was not found in rats treated with castor oil for 3 d. Moreover, 5-HT concentration in the midbrain significantly decreased in rats that acquired the adaptability for the occurrence of diarrhea. These data present a new finding that the occurrence of diarrhea or acquisition of adaptability for diarrheal occurrence affects the central histaminergic or serotonergic neuron system.

[Determination of disaccharidase activity in rat serum, bile, urine and various tissues by high-performance liquid chromatography with differential refractometric detection].

A simple and high sensitive method for the determination of disaccharidase in various biological samples of rats by high-performance liquid chromatography (HPLC) with a differential refractometric detection was developed. This method, as compared with the Dahlqvist method, has the following advantages; 1) There is no necessity for the elimination of biological components which have an influence on the determination of glucose. 2) Only a little enzyme sample is used. 3) The detection limit of a reaction product, glucose, by the HPLC method is about 10 times higher than that by the Dahlqvist method. 4) The maltase activity in the small intestinal mucosa estimated by HPLC method is positively correlated with that estimated by the Dahlqvist method (r = 0.9661, p less than 0.001, n = 8). 5) This method developed in the present study is applicable to not only the small intestinal mucosa, but also serum, bile, urine and various tissues.