Pharmacokinetics of [6]-shogaol, a pungent ingredient of Zingiber officinale Roscoe (Part I).

To investigate the pharmacokinetics of [6]-shogaol, a pungent ingredient of Zingiber officinale Roscoe, the pharmacokinetic parameters were determined by using (14)C-[6]-shogaol (labeled compound) and [6]-shogaol (non-labeled compound). When the labeled compound was orally administered to rats, the maximum plasma concentration (C (max)) and the area under the curve (AUC) of plasma radioactivity concentration increased in a dose-dependent manner. When the labeled compound was orally administered at a dose of 10 mg/kg, 20.0 + or - 1.8% of the radioactivity administered was excreted into urine, 64.0 + or - 12.9% into feces, and 0.2 + or - 0.1% into breath. Thus, more of the radioactivity was excreted into feces than into urine, and almost no radioactivity was excreted into breath. Furthermore, when the labeled compound was orally administered at a dose of 10 mg/kg, cumulative biliary radioactivity excretion over 48 h was 78.5 + or - 4.5% of the radioactivity administered, and cumulative urinary radioactivity excretion over 48 h was 11.8 + or - 2.7%, showing that about 90% of the dose administered orally was absorbed from the digestive tract and most of the fecal excretion was via biliary excretion. On the other hand, when the non-labeled compound [6]-shogaol was orally administered, the plasma concentration and biliary excretion of the unchanged form were extremely low. When these results are combined with those obtained with the labeled compound, it would suggest that [6]-shogaol is mostly metabolized in the body and excreted as metabolites.

Effects of Kampo medicines on CYP and P-gp activity in vitro.

The Kampo medicines are more and more often used in recent years, usually together with the Western drugs. The need for the investigation of drug interactions between Kampo medicines and Western drugs are, therefore, widely recognized. In the present study, the effects of 3 Kampo medicines (Rikkunshito, Yokukansan and Boiogito) on the activity of cytochrome P450 (CYP), a superfamily of drug-metabolizing enzymes, were investigated in an in vitro study using human CYP recombinants. Their effects on the P-glycoprotein (P-gp), one of the major drug transporters, were also evaluated by the ATPase assay using human P-gp membranes and verapamil as a substrate. The inhibition rate of Rikkunshito, Yokukansan and Boiogito on human CYP3A4, 2C9, 2C19, 2D6 and 2E1 was less than 50% at the concentrations below 0.1 mg/ml except for the inhibition of CYP2D6 by Boiogito. Furthermore, none of the Kampo medicines affected the ATPase activity at the concentrations lower than 0.1 mg/ml, either in the absence or presence of verapamil, indicating their low inhibitory potency against P-gp. These findings indicate that Rikkunshito, Yokukansan and Boiogito are unlikely to cause clinically relevant drug interactions involving the inhibition of major CYP isozymes and P-gp.

Glycycoumarin from Glycyrrhizae Radix acts as a potent antispasmodic through inhibition of phosphodiesterase 3.

Glycyrrhizae Radix is used to treat abdominal pain as a component of Shakuyaku-kanzo-to, a traditional Chinese medicine formulation. We aim at clarifying the antispasmodic principles of Glycyrrhizae Radix, and consequently isolated glycycoumarin as a potent relaxant on the carbamylcholine (CCh)-induced contraction of mouse jejunum. In this paper we investigated the effects and the action mechanism of glycycoumarin on the contraction of mouse jejunum. Glycycoumarin inhibited the contraction induced by various types of stimulants, such as CCh, KCl, BaCl(2), and A23187 (calcium ionophore III) with IC(50) values of 2.93+/-0.94 micromol/l (1.08+/-0.35 microg/ml), 2.59+/-0.58 micromol/l (0.95+/-0.29 microg/ml), 4.09+/-1.82 micromol/l (1.51+/-0.67 microg/ml) and 7.39+/-5.19 micromol/l (2.72+/-1.91 microg/ml), respectively, with a potency similar to that of papaverine (a representative antispasmodic for smooth muscle). Furthermore, pretreatment with glycycoumarin enhanced the relaxation induced by forskolin on CCh-evoked contraction, similar to that by pretreatment with IBMX, a non-specific inhibitor of phosphodiesterases (PDEs). Pretreatment with glycycoumarin also enhanced the relaxation effect of rolipram, a specific inhibitor of PDE isozyme 4, as pretreatment with milrinone, a specific inhibitor of isozyme 3, did. Moreover, the effect of glycycoumarin was associated with dose-dependent accumulation of cAMP, but not cGMP, in mouse jejunum. These results indicate that glycycoumarin has an inhibitory effect on smooth muscle contraction induced by various types of stimulants through the inhibition of PDEs, especially isozyme 3, followed by the accumulation of intracellular cAMP.

The influence of the sennosides on absorption of glycyrrhetic acid in rats.

In the course of our clinical studies of Kampo medicine (traditional Japanese medicines), we observed the pharmacokinetic interactions between two herbs. When Onpito (TJ-8117, Kampo medicine) containing licorice and rhubarb was administered orally to human subjects, we observed that the AUC(0-lim) and Cmax of glycyrrhetic acid (GA) in plasma were lower than those treated with other Kampo medicines containing licorice. In this study, we demonstrate the pharmacokinetic interactions of GA derived from glycyrrhizinic acid (GL) in licorice and anthraquinones derived from rhubarb. To our knowledge, this is the first report to investigate the pharmacokinetic interactions between two herbs. When GL was orally co-administrated to rats with a non-effective dose of sennoside A having purgative activity, the AUC(0-lim) and Cmax of GA decreased. In addition, sennoside A did not affect the metabolism of GL by the intestinal bacteria in vitro. In the examination using an in situ loop of rat colon, the remaining ratio of GA rose drastically by the co-administration of sennoside A, sennidin A and rhein. Observed inhibition activity of these anthraquinones on GA absorption depended on the concentration of the components added. The maximum inhibition ratio was approximately 75% by rhein, 60% by sennoside A and 25% by sennidin A. We conclude that the decrease of the pharmacokinetic parameters of GA in human plasma observed in the clinical study of TJ-8117 is attributable to an interactive action of absorption from the intestinal tract by anthraquinones contained in or derived from rhubarb.

Pharmacokinetic and pharmacodynamic profiles of the antitussive principles of Glycyrrhizae radix (licorice), a main component of the Kampo preparation Bakumondo-to (Mai-men-dong-tang).

We examined the pharmacokinetic and pharmacodynamic properties of liquiritin apioside, a main antitussive component of Glycyrrhizae radix (licorice), with regard to its antitussive effect in guinea pigs. The peak plasma concentration of the unchanged compound was observed 15 min after the administration of liquiritin apiosaide. The plasma concentration then gradually decreased and was almost undetectable 4 h after administration. Liquiritigenin, a des-glycoside of liquiritin apioside, appeared in the plasma 2 h after the administration of liquiritin apioside and remained for more than 6 h after administration. The plasma concentration of unchanged liquiritigenin was observed 15 min after administration and then gradually increased for more than 6 h after administration. When the antitussive effects of liquiritin apioside, liquiritin and liquiritigenin, at respective doses of 30 mg/kg, p.o., were examined 1 h after administration, liquiritin apioside and liquiritigenin caused a significant reduction in the number of capsaicin-induced coughs. However, at the same dose, liquiritin had no significant effect on the number of capsaicin-induced coughs. On the other hand, when the antitussive effects of liquiritin apioside, liquiritin and liquiritigenin, at doses of 30 mg/kg, p.o., were examined 4 h after administration, each caused a more than 40% reduction in the number of capsaicin-induced coughs. The present results suggest that G. radix (licorice) may produce a persistent antitussive effect, and that liquiritin apioside plays an important role in the earlier phase, while liquiritigenin, which is a metabolite of liquiritin apioside and liquiritin, plays an important role in the late phase.

Permeability of the flavonoids liquiritigenin and its glycosides in licorice roots and davidigenin, a hydrogenated metabolite of liquiritigenin, using human intestinal cell line Caco-2.

The present investigation focused on the transepithelial flux of liquiritigenin (LG), davidigenin (DG), liquiritin (LQ), and liquiritin apioside (LA) using the human colonic cell line Caco-2 as a model of human intestinal absorption. Apparent permeability coefficients (Papp) for the apical to basolateral flux of LG and DG were (16.0 +/- 0.727) x 10(-6) cm/s and (18.2 +/- 1.67) x 10(-6) cm/s, respectively. These Papp were higher than that of the transcellular transport marker propranolol (13.5 +/- 0.34) x 10(-6) cm/s (P < 0.01). Papp for the apical to basolateral flux of LQ and LA were (0.26 +/- 0.12) x 10(-6) cm/s and (0.075 +/- 0.005) x 10(-6) cm/s, respectively. These Papp were lower than that of the paracellular transport marker mannitol (0.64 +/- 0.04) x 10(-6) cm/s (LG, P < 0.01; LA, P < 0.001). These data suggested excellent absorption of LG and DG through the human intestinal epithelial cell line. On the contrary, poor absorption of LQ and LA was expected due to the little transepithelial flux of these compounds in the human colonic cell line Caco-2.

Absorption, distribution and excretion of 3H-labeled cephaeline- and emetine-spiked ipecac syrup in rats.

The maximum plasma radioactivity levels of tritium (3H)-labeled cephaeline, (24.3, 28.7 and 40.6 ng eq./mL) were reached at 2.00-3.33 hours following oral dosing of ipecac syrup. The maximum plasma radioactivity levels of 3H-emetine (2.71, 6.47 and 9.62 ng eq./mL) were reached at 1.08-2.33 hours following ipecac syrup administration. The Cmax values of 3H-cephaeline were followed by a biexponential decrease with half-lives t 1/2(lambda z) of 3.45-9.40 hours. On the other hand, the t 1/2 (lambda z)of 3H-emetine were 65.4-163 hours, which revealed a biexponential decrease. The radioactivity of both tritium-labeled compounds was distrbuted maximally in most tissues at 24 hours. For 3H-cephaeline, the maximum radioactivity levels in tissues were approximately 100-150 times greater than in plasma. For 3H-emetine, the radioactivity levels in tissues were approximately 1000-3000 times greater than in plasma. Tissue radioactivity levels decreased at a substantially slower rate than that observed in plasma. Tissue radioactivity of 3H-emetine decreased more slowly than that of 3H-cephaeline. For 3H-cephaeline, the cumulative biliary excretion of radioactivity was 57.5% at 48 hours. The cumulative urinary and fecal excretion of radioactivity in these rats was 16.5% and 29.1%, respectively, of the dose at 48 hours following dosing. For 3H-emetine, the cumulative biliary excretion of radioactivity was 12.5% at 48 hours. The cumulative urinary and fecal excretion of radioactivity was 9.4% and 34.1%, respectively, of the administered dose at 48 hours. The radioactivity level of 3H-emetine remaining in the carcasses at 48 hours was equivalent to approximately 50% of the dose. A portion of each tritium-labeled compound was subjected to entero-hepatic circulation. Thus, the absorption rate of 3H-cephaeline and 3H-emetine was estimated to be approximately 70% on the basis of the data obtained from excretion studies. There was no difference in the absorption process between these two compounds. However, the difference was admitted in the biliary clearance, which is the main excretion route of both compounds. Delayed excretion of 3H-emetine may be primarily due to its resorption as related to entero-hepatic circulation and tissue retention. This study has determined the absorption, distribution and excretion of 3H-cephaeline and 3H-emetine in rats.

Biotransformation of the ipecac alkaloids cephaeline and emetine from ipecac syrup in rats.

The metabolism of cephaeline and emetine, which are the primary active components of ipecac syrup, were investigated in rats. Cephaeline-6'-O-glucuronide was found to be a biliary metabolite of cephaeline. Cephaeline (6'-O-demethylemetine) and 9-O-demethylemetine were observed to be enzyme-hydrolyzed biliary metabolites of emetine. Cephaeline was conjugated to glucuronide, while emetine was demethylated to cephaeline and 9-0-demethylemetine, and may be conjugated to glucuronides afterwards. Urine, feces and bile were collected from rats within 48 hours following the administration of ipecac syrup containing tritium (3H)--labeled cephaeline or emetine. Metabolites were separated and quantified by thin layer chromatography (TLC) or high-performance liquid chromatography (HPLC). Biliary and urinary excretion rates of 3H-cephaeline were 57.5% and 16.5% of the dose, respectively. Cephaeline-6'-O-glucuronide was comprised 79.5% of biliary radioactivity and 84.3% of urinary radioactivity. Unchanged cephaeline was detected in 42.4% of the dose in feces. Biliary excretion rate of 3H-emetine was 6.9% of the dose. Emetine, cephaeline and 9-0-demethylemetine comprised 5.8%, 43.2% and 13.6% in hydrolyzed bile, respectively. There were no emetine-derived metabolites in urine or feces. The occurrence of unchanged emetine was 6.8% and 19.7% of the dose in urine and feces, respectively.