Influence of food on the gastric motor effect of the Kampo medicine rikkunshito in rat.

BACKGROUND: Rikkunshito, one of the Kampo medicines, is widely prescribed as a remedy for various upper gastrointestinal syndromes. The effect of rikkunshito is related to endogenous ghrelin and its active ingredient atractylodin enhances ghrelin receptor signaling. Kampo medicines are traditionally administered before or between meals; however, no definitive benefit of the timing of administration has been proven yet. To clarify the influence of food on the pharmacological action of rikkunshito, we investigated the gastric motor activity and pharmacokinetic profiles of atractylodin after the administration of rikkunshito in fasted and fed rats. METHODS: Phase III-like contractions in the gastric antrum after an injection of ghrelin were measured using a strain gauge force transducer. Rikkunshito was administered to rats during fasting or after a nutrient test meal. Ghrelin was injected 30 minutes later and gastric motility was evaluated. Furthermore, after rikkunshito administration, the pharmacokinetic profiles of atractylodin in the plasma and brain of fasted and free-fed rats were assessed. KEY RESULTS: Rikkunshito administration potentiated ghrelin-induced phase III-like contractions under fasting conditions. This effect was attenuated in animals fed a test meal. Atractylodin was detected pharmacokinetically in the plasma and brain after rikkunshito administration in rats, and free-fed rats exhibited a decreased maximum concentration of plasma atractylodin and a delayed time to reach the maximum concentration. CONCLUSIONS & INFERENCES: We show that the pharmacological action of rikkunshito is influenced by food in rats. The efficacy of rikkunshito may be associated with decreased absorption of its active ingredient atractylodin when food is in the stomach.

Administration of exogenous acylated ghrelin or rikkunshito, an endogenous ghrelin enhancer, improves the decrease in postprandial gastric motility in an acute restraint stress mouse model.

BACKGROUND: Physical or psychological stress causes functional disorders in the upper gastrointestinal tract. This study aims to elucidate the ameliorating effect of exogenous acylated ghrelin or rikkunshito, a Kampo medicine which acts as a ghrelin enhancer, on gastric dysfunction during acute restraint stress in mice. METHODS: Fasted and postprandial motor function of the gastric antrum was wirelessly measured using a strain gauge force transducer and solid gastric emptying was detected in mice exposed to restraint stress. Plasma corticosterone and ghrelin levels were also measured. To clarify the role of ghrelin on gastrointestinal dysfunction in mice exposed to stress, exogenous acylated ghrelin or rikkunshito was administered, then the mice were subjected to restraint stress. KEY RESULTS: Mice exposed to restraint stress for 60 min exhibited delayed gastric emptying and increased plasma corticosterone levels. Gastric motility was decreased in mice exposed to restraint stress in both fasting and postprandial states. Restraint stress did not cause any change in plasma acylated ghrelin levels, but it significantly increased the plasma des-acyl ghrelin levels. Administration of acylated ghrelin or rikkunshito improved the restraint stress-induced delayed gastric emptying and decreased antral motility. Ameliorating effects of rikkunshito on stress-induced gastric dysfunction were abolished by simultaneous administration of a ghrelin receptor antagonist. CONCLUSIONS & INFERENCES: Plasma acylated/des-acyl ghrelin imbalance was observed in acute restraint stress. Supplementation of exogenous acylated ghrelin or enhancement of endogenous ghrelin signaling may be useful in the treatment of decreased gastric function caused by stress.

The Traditional Japanese Medicine Rikkunshito Promotes Gastric Emptying via the Antagonistic Action of the 5-HT(3) Receptor Pathway in Rats.

The traditional Japanese medicine rikkunshito ameliorates the nitric oxide-associated delay in gastric emptying. Whether rikkunshito affects gastric motility associated with 5-hydroxytryptamine (serotonin: 5-HT) receptors or dopamine receptors is unknown. We examined the effects of rikkunshito on the delay in gastric emptying induced by 5-HT or dopamine using the phenol red method in male Wistar rats. 5-HT (0.01-1.0 mg kg(-1), i.p.) dose dependently delayed gastric emptying, similar to the effect of the 5-HT(3) receptor agonist 1-(3-chlorophenyl) biguanide (0.01-1.0 mg kg(-1), i.p.). Dopamine also dose dependently delayed gastric emptying. The 5-HT(3) receptor antagonist ondansetron (0.04-4.0 mg kg(-1)) and rikkunshito (125-500 mg kg(-1)) significantly suppressed the delay in gastric emptying caused by 5-HT or 1-(3-chlorophenyl) biguanide. Hesperidin (the most active ingredient in rikkunshito) suppressed the 5-HT-induced delayed gastric emptying in a dose-dependent manner, the maximum effect of which was similar to that of ondansetron (0.4 mg kg(-1)). The improvement obtained by rikkunshito or ondansetron in delaying gastric emptying was completely blocked by pretreatment with atropine. Rikkunshito appears to improve delay in gastric emptying via the antagonistic action of the 5-HT(3) receptor pathway.

Metabolism of ipecac alkaloids cephaeline and emetine by human hepatic microsomal cytochrome P450s, and their inhibitory effects on P450 enzyme activities.

In this study, we identified the metabolites and the CYP forms that are specifically involved in emetine O-demethylation in human liver microsomes, and cleared the inhibitory potential of cephaeline and emetine on the activity of the major drug-metabolizing CYP enzymes. Incubation of emetine with human liver microsomes yielded three metabolites identified by using HPLC by comparison of the retention time with the authentic sample of cephaeline, 9-O-demethylemetine and 10-O-demethylemetine. CYP3A4 and CYP2D6 were able to metabolize emetine to cephaeline and 9-O-demethylemetine, and CYP3A4 also participated in metabolizing emetine to 10-O-demethylemetine. Cephaeline and emetine inhibited probe substrates metabolism. IC50 for cephaeline against CYP2D6 and CYP3A4 were 121 and 1000 microM, respectively. For the emetine, CYP2D6 and CYP3A4 were 80 and 480 microM, respectively. Inhibition constants (Ki) for both compounds on the CYP2D6 and CYP3A4 activities were determined by graphic analysis of Dixon plots at various concentrations. The obtained Ki values of cephaeline for CYP2D6 and CYP3A4 were 54 and 355 microM, respectively, and the values of emetine were 43 and 232 microM, respectively. We concluded that these in vitro inhibitions of cephaeline and emetine would hardly increase plasma concentrations of co-administered drugs in clinical therapy.

High-performance liquid chromatographic assay with fluorescence detection for the determination of cephaeline and emetine in human plasma and urine.

A high-performance liquid chromatographic assay method for the quantitation of ipecac alkaloids (cephaeline and emetine) in human plasma and urine is described. Human plasma or urine was extracted with diethylether under alkaline conditions following the addition of an internal standard. Concentrations of alkaloids and internal standard were determined by octadecylsilica chromatographic separation (Symmetry C18 columns, plasma analysis; 15 cmx4.6 mm I.D., 5 microm particle size, urine analysis; 7.5 cmx4.6 mm I.D., 5 microm particle size). The mobile phase consisted of buffer (20 mmol/l 1-heptanesulfonic acid sodium salt, adjusted to pH 4.0 with acetic acid)-methanol (51:49, v/v). Eluate fluorescence was monitored at 285/316 nm. The lowest quantitation limits of cephaeline and emetine were 1 and 2.5 ng/ml, respectively, in plasma, and 5 ng/ml in urine. Intra- and inter-day relative standard deviations were below 15%. The assay is sensitive, specific and applicable to pharmacokinetic studies in humans.