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Interaction between Shaoyao-Gancao-Tang and a laxative with respect to alteration of paeoniflorin metabolism by intestinal bacteria in rats.

Abstract

Shaoyao-Gancao-Tang (SGT), a traditional Chinese herbal medicine (Kampo formulation) containing Shaoyao (Paeoniae Radix) and Gancao (Glycyrrhizae Radix), is co-administered with laxative sodium picosulfate as a premedication for relieving the pain accompanying colonoscopy. Paeoniflorin (PF), an active glycoside of SGT, is metabolized into the antispasmodic agent paeonimetabolin-I (PM-I) by intestinal bacteria after oral administration. The objective of the present study was to investigate whether the co-administered laxative (sodium picosulfate) influences the metabolism of PF to PM-I by intestinal bacteria. We found that the PF-metabolizing activity of intestinal bacteria in rat feces was significantly reduced to approximately 34% of initial levels by a single sodium picosulfate pretreatment and took approximately 6 days to recover. Repeated administration of SGT after the sodium picosulfate pretreatment significantly shortened the recovery period to around 2 days. Similar results were also observed for plasma PM-I concentration. Since PM-I has muscle relaxant activity, the present results suggest that repetitive administration of SGT after sodium picosulfate pretreatment might be useful to relieve the pain associated with colonoscopy.

[c] 2006 Elsevier GmbH. All rights reserved.

Keywords: Drug-drug interaction; Intestinal bacteria; Paeoniflorin; Laxative; Traditional Chinese formulation; Shaoyao Gancao-Tang

Introduction

In Japan, freeze-dried preparations of traditional Chinese herbal medicine (Kampo formulations for ethical use) are used within the realm of conventional medicine, rather than as complementary or alternative treatments as in the USA. Kampo formulations are therefore often used in combination with synthetic drugs (Akase et al., 2002). As the interactions between modern drugs and Chinese medicinal herbs have aroused much concern (Cheng et al., 2003), it is very important to clarify interactions when such agents are co-administered.

To date, although the influence of Kampo formulations on the pharmacokinetics of synthetic drugs has been studied (Ohnishi et al., 2002), the literature contains few reports of the influence of synthetic drugs on the pharmacokinetics of the active constituents of Kampo formulations. It is reported that the water-soluble glycosides in Kampo formulations do not normally permeate the gut mucosa and are therefore absorbed only after being metabolized by intestinal bacteria (Kobashi et al., 1992). Therefore, investigation of the intestinal metabolism of such glycosides before absorption from the gut may provide valuable information regarding the interaction between Kampo formulations and synthetic drugs. In this regard, we previously reported the influence of certain antibacterial drugs on the metabolic activity of the intestinal bacteria that metabolize glycyrrhizin (He et al., 2001) and paeoniflorin (PF) (He et al., 2003a) in co-administered Shaoyao-Gancao-Tang (SGT).

SGT (shakuyakukanzoto in Japanese), composed of Shaoyao (Paeoniae Radix) and Gancao (Glycyrrhizae Radix), is a widely used Kampo formulation for treating abdominal spasmodic pain accompanying acute gastroenteritis (Katsura, 1995). The clinical antispasmodic effects of SGT on muscle cramps accompanying liver cirrhosis have also been verified by a double-blind randomized placebo-controlled trial (Kumada et al., 1999). The antispasmodic effects of Paeoniae Radix (and those of SGT) are reported to be partially accounted for by paeonimetabolin-I (PM-I) (Abdel-Hafez et al., 1999). This is derived from PF, one of the major glycosides in Paeoniae Radix, by intestinal bacteria such as Bacteroides fragilis (Shu et al., 1987).

SGT is also used as a premedication for relieving pain accompanying colonoscopy (Arai et al., 1994). In this context, it is often used in combination with a laxative such as sodium picosulfate, a colon-cleansing agent (Fork et al., 1982). As a part of our research interest in the study of pharmacological evidences for the use of Kampo formulations including SGT, the present study was designed to examine the influence of a co-administered laxative (sodium picosulfate) on the metabolism of PF to PM-I by intestinal bacteria and the alteration of the bioavailability of PM-I resulting from SGT.

Materials and methods

Materials

The freeze-dried extract of SGT was prepared as previously reported (He et al., 2001). In brief, a mixture of 6g each of Shaoyao and Gancao was boiled in water (600 ml) for 40min to obtain the water extract, which was filtered and freeze-dried into powder (yield: 4.02 [+ or -] 0.06 g, which is a common daily dose for adult humans). To assure the homogeneity of the formulation and to prepare consistent batches, the HPLC profile (Fig. 1) of the SGT extract was analyzed. Voucher specimens of Shaoyao (produced in Japan) and Gancao (imported from China: Dongbei-Gancao in Chinese) were deposited in the Department of Kampo-Pharmaceutics, Institute of Natural Medicine, University of Toyama.

[FIGURE 1 OMITTED]

PF and sodium picosulfate were purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). All of the other chemicals and solvents used were of analytical and/or HPLC grade.

Administration of sodium picosulfate and SKT extract to rats

Male Wistar rats (8 weeks old, approx. 250 g, n = 5 for each group) purchased from Japan SLC Inc. (Hamamatsu, Japan) were maintained on a 12-h light-dark cycle at 21-24 [degrees]C and were given free access to water and standard laboratory chow throughout the study. All animal experiments were carried out in accordance with the Guidelines of the Animal Care and Use Committee of the University of Toyama, approved by the Japanese Association of Laboratory Animal Care.

Sodium picosulfate (50mg/kg, 10 times the common human daily dose) was administered orally to rats on day 0. Five hours after sodium picosulfate pretreatment, SGT extract was administered orally twice a day, at a total daily dose of 645mg/kg (10 times the common human daily dose) as shown in Fig. 2.

Determination of diarrhea (Exp. 1. in Fig. 2)

Fecal samples were collected according to the specific schedule shown in Fig. 2. Fecal water content was determined by calculating the weight of fecal samples before and after drying at 120 [degrees]C for 4h. Diarrhea was defined as a fecal water content of 80% or more.

Determination of PF-metabolizing activity in rat feces (Exp. 2. in Fig. 2)

The PF-metabolizing activity (biotransformation rate of PF into PM-I) of intestinal bacteria in rat feces was estimated by measuring the rate of formation of 8-phenylthio-paeonimetabolin-I (PT-PM-I) from PF, which was determined using our previously developed HPLC method (He et al., 2002). This method is based on the finding that the rate of metabolizing PF into PM-I by intestinal bacteria is equivalent to that of metabolizing PF into PT-PM-I, a compound produced by incubating PF with fecal suspension in the presence of phenylmercaptan (thiophenol, Fig. 3). Fecal samples were collected at 9 am, 2 pm, and 7 pm on day 0 and at 9 am from days 1-9. Initial levels of PF-metabolizing activity were measured from the fecal samples collected at 9 am on day 0; before any treatment.

Recovery time (days) was defined as the average number of days between activity being reduced to 70% or less of the initial level to recovery to 90% or more (Abe et al., 2001).

[FIGURE 2 OMITTED]

Determination of plasma PM-I concentration (Exps. 3-5. in Fig. 2)

As shown in Fig. 2, blood samples were collected at 18:00 on day 0 and at 13:00 from days I to 9; i.e. 4h after SGT administration. This timing was chosen as plasma PM-I concentration reaches its peak ([C.sub.max]) 4h after SGT administration (He et al., 2003a). Initial levels of plasma PM-I were measured from the first blood samples collected at 13:00 on day 0 from normal rats.

Treatment of collected blood samples and determination of plasma PM-I concentration were performed as previously reported (He et al., 2003a) using an enzyme immunoassay method (Hattori et al., 1996). Maximum plasma concentration ([C.sub.max]) and time to reach [C.sub.max] ([t.sub.max]) were determined directly from actual drug levels in plasma. The area under the mean concentration vs. time curve from zero to 24 h ([AUC.sub.0-24h]) was calculated using the trapezoidal rule.

Statistical analysis

The difference between values before and after treatment was statistically analyzed using the paired two-tailed Student's t-test. Comparisons between two groups and among more than two groups were performed using the unpaired two-tailed Student's t-test and one-way analysis of variance (ANOVA) followed by Tukey's post-hoc test, respectively. Differences were considered statistically significant at p < 0.05.

[FIGURE 3 OMITTED]

[FIGURE 4 OMITTED]

Results

Determination of diarrhea (Exp. 1. in Fig. 2)

After a single pretreatment with sodium picosulfate, diarrhea (fecal water content >80%) was observed and continued for 2.0 [+ or -] 0.5 day. The group receiving repeated SGT after the sodium picosulfate pretreatment had a similar duration of diarrhea (2.2 [+ or -] 0.7 day). These results indicate that the laxative effect of sodium picosulfate was not affected by co-administration of SGT.

Alteration of PF-metabolizing activity in feces (Exp. 2. in Fig. 2)

PF-metabolizing activity of intestinal bacteria in rat feces was significantly reduced (to 33.8% of initial levels) 5 h after the sodium picosulfate pretreatment and did not recover until day 6 (6.0 [+ or -] 0.5 day) (Fig. 4). However, the recovery period was significantly shortened to approximately 2 days (1.8 [+ or -] 0.4 day) by repeated administration of SGT following the sodium picosulfate pretreatment.

Plasma PM-I concentration (Exps. 3-5. in Fig. 2)

Fig. 5 shows changes in daily plasma PM-I concentration (4h after the first SGT administration each day: equivalent to [C.sub.max]) by sodium picosulfate pretreatment, with or without repetitive SGT. In both groups, plasma PM-I concentration on day 0 (9h after sodium picosulfate pretreatment and 4 h after SGT administration) was significantly reduced to 8.3% of initial levels. In the group not administered SGT, PM-I level remained markedly reduced (19.2% of initial levels) on day 2 and did not recover to initial levels until day 6. In the group repeatedly administered SGT, however, PM-I level recovered to initial levels on day 2 (108% of initial levels).

[FIGURE 5 OMITTED]

[FIGURE 6 OMITTED]

As shown in Fig. 6 and Table 1, from a single dose of SGT administered 5h after the sodium picosulfate pretreatment, the [C.sub.max] of PM-I was significantly reduced to approximately 5.3% of control levels (no sodium picosulfate pretreatment) (1.47 [+ or -] 0.10 vs. 0.08 [+ or -] 0.01 [micro]g/ml) and the [AUC.sub.0-24h] of PM-I was significantly reduced to approximately 16.1% of control levels (7.81 [+ or -] 0.63 vs. 1.26 [+ or -] 0.13 [micro]g h/ml). These reductions (13.6% and 49.6% of control levels, respectively) remained significant when SGT was administered 2 days after sodium picosulfate pretreatment, although [C.sub.max] and [AUC.sub.0-24h] were significantly increased when compared with those obtained 5h after sodium picosulfate pretreatment. In the group repeatedly administered SGT following sodium picosulfate pretreatment, however, [C.sub.max] (1.76 [+ or -] 0.05 [micro]g/ml) and [AUC.sub.0-24h] (10.58 [+ or -] 1.01 [micro]g h/ml) on day 2 recovered to levels similar to those observed in the control group on day 0 ([C.sub.max]: 1.47 [+ or -] 0.10 [micro]g/ml; [AUC.sub.0-24h:] 7.81 [+ or -] 0.71 [micro]g h/ml).

Daily plasma PM-I concentration was well correlated (r = 0.94) with the daily PF-metabolizing activity of intestinal bacteria in rat feces (Fig. 7).

Discussion

In contrast to synthetic drugs, the efficacy of numerous Kampo formulations is generally related to the presence of glycosides (e.g. glycyrrhizin and PF in SGT), which are difficult for human digestive enzymes to metabolize (Kobashi et al., 1992). Absorption therefore occurs after these agents are metabolized (hydrolyzed) to bioactive aglycones by intestinal bacteria (Kobashi et al., 1992). The glycoside-metabolizing activity of intestinal bacteria is affected by co-administration of certain synthetic drugs such as antibacterial drugs (He et al., 2003a) and laxatives (Goto et al., 2005). The role of intestinal bacteria in pharmacokinetic interactions between Kampo formulations and synthetic drugs should therefore be reevaluated. In this regard, the present study investigated whether co-administration of a laxative (sodium picosulfate), a colon-cleansing drug used in colonoscopy, influences the metabolism of PF to PM-I by intestinal bacteria.

As shown in Fig. 4, the PF-metabolizing activity of intestinal bacteria in rat feces was reduced to approx. 34% of initial levels 5h after the sodium picosulfate pretreatment. Although this reduction was significant, it was not as serious as that caused by the antibacterial drugs amoxicillin and metronidazole, which reduced PF-metabolizing activity to 16% of initial levels (He et al., 2003a).

[FIGURE 7 OMITTED]

Sodium picosulfate pretreatment caused a similar reduction and recovery of intestinal bacteria PF-metabolizing activity (Fig. 4) to that seen for glycyrrhizin-metabolizing activity of intestinal bacteria among rats administered sodium picosulfate pretreatment (Goto et al., 2005). Previous studies have indicated that the [C.sub.max] and AUC of glycyrrhetic acid derived from glycyrrhizin by intestinal bacteria were similar in rats and humans (Bandoh et al., 2000), when rats were orally administered a single dose of SGT at 10 times the human dose (He et al., 2001). The rat is therefore considered a reasonable model to reflect the metabolism of glycyrrhizin by human intestinal bacteria. We therefore hypothesized that this would hold true for PM-I.

Although PF-metabolizing activity took 6 days to return to initial levels, the repeated administration of SGT following the sodium picosulfate pretreatment accelerated the recovery period to 2 days. A previously postulated mechanism for this restorative effect is that PF and other ingredients of SGT might enhance the population and ability of intestinal bacteria capable of metabolizing PF into PM-I (He et al., 2003b).

As shown in Fig. 5, when SGT was repeatedly administered, the recovery profile of plasma PM-I concentration was similar to that of PF-metabolizing activity (Fig. 4). Repeated administration of SGT appears to have a similar restorative effect on the laxative-influenced pharmacokinetics of PM-I as it does on the antibiotic-altered pharmacokinetics of PM-I by drugs (He et al., 2003b).

As shown in Table 1, the plasma concentration and [AUC.sub.0-24h] of PM-I in the group repeatedly administered SGT were significantly greater than those in the group without repeated administration of SGT. [AUC.sub.0-24h] of PM-I in the repetitive SGT group on day 2 recovered to a similar level to that observed in the control group (no sodium picosulfate pretreatment) on day 0. Fig. 7 shows that daily plasma PM-I concentration was well correlated with daily PF-metabolizing activity of intestinal bacteria. A similar correlation was also observed between plasma PM-I concentration and PF-metabolizing activity, which were both reduced by antibiotic treatment (He et al., 2003a).

The antispasmodic and analgesic effects of SGT have been observed clinically on directly applying SGT to the region of colon spasm during colonoscopy (Ai et al., 2003). In this case, the effects of SGT were considered due to direct inhibition of GI tract contraction by ingredients contained in the extract, rather than by the bioactive metabolites transformed from glycosides by intestinal bacteria. Studies of the active ingredients in SGT and its two constituent crude drugs are ongoing (Sato et al., 2006).

It was reported that 12.6% of 1021 patients had abdominal pain after taking sodium picosulfate before colonoscopy (Ishikawa et al., 2004). Since SGT has potent effect in the treatment of various acute abdominal pains (Katsura, 1995), it is considered that the pain caused by sodium picosulfate will be also relieved by the use of SGT.

In conclusion, the present study examined the influence of sodium picosulfate, a laxative, on the plasma concentration of the antispasmodic metabolite PM-I derived from PF contained in SGT by the metabolism of intestinal bacteria. PF-metabolizing activity and plasma PM-I concentration were significantly reduced by a single sodium picosulfate pretreatment. Repeated administration of SGT 5h after this sodium picosulfate pretreatment shortened the recovery period. Since PM-I possess muscle relaxation activity, these results suggest that after pretreatment with sodium picosulfate for colonoscopy, repeated administration of SGT may relive pain due to its enhancement of PM-I bioavailability.

Acknowledgments

The authors are indebted to Prof. M. Hattori (Toyama Medical and Pharmaceutical University) for his guidance in enzyme immunoassay of paeonimetabolin-I. This study was supported in part by a Grant-in-Aid for the 21st Century COE Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

References

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Ju-Xiu He (a), Emi Goto (a), Teruaki Akao (b,*), Tadato Tani (a,c)

(a) Institute of Natural Medicine, Toyama, Japan

(b) Toyama Medical and Pharmaceutical University, Faculty of Pharmaceutical Sciences, 2630 Sugitani, Toyama, Japan

(c) 21st Century COE Program, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan

*Corresponding author. Tel: +81 76 434 2281x2906; fax: +81 76 434 4656.

E-mail address: ta0113@ms.toyama-mpu.ac.jp (T. Akao).
Table 1. Pharmacokinetic parameters of paeonimetabolin-I (PM-I) derived
from Shaoyao-Gancao-Tang (SGT) administered 5 h or 2 days after
pretreatment with sodium picosulfate (Pico) in rats

 5 h after Pico pretreatment
 SGT with Pico
Parameter SGT alone control (a) pretreated-1 (b)

[t.sub.max] (h) 4.0 [+ or -] 0.0 24.0 [+ or -] 0.0*
[C.sub.max] ([micro]g/ml) 1.47 [+ or -] 0.10 0.08 [+ or -] 0.01*
([C.sub.max]%) (e) 100% 5.3 [+ or -] 0.5
[AUC.sub.0-24h] 7.81 [+ or -] 0.71 1.26 [+ or -] 0.13*
 ([micro]g h/ml)
([AUC.sub.0-24h]%) (e) 100 16.1 [+ or -] 1.7

 2 d after Pico pretreatment
 SGT with Pico
Parameter pretreated-2 (c)

[t.sub.max] (h) 13.2 [+ or -] 4.4*
[C.sub.max] ([micro]g/ml) 0.20 [+ or -] 0.02 (*,[dagger])
([C.sub.max]%) (e) 13.6 [+ or -] 1.2
[AUC.sub.0-24h] 3.88 [+ or -] 0.38 (*,[dagger])
 ([micro]g h/ml)
([AUC.sub.0-24h]%) (e) 49.6 [+ or -] 4.9

 2 d after Pico pretreatment
 SGT with Pico
Parameter pretreated-3 (d)

[t.sub.max] (h) 4.0 [+ or -] 0.0 ([dagger],[double dagger])
[C.sub.max] ([micro]g/ml) 1.76 [+ or -]
 0.05 ([dagger],[double dagger])
([C.sub.max]%) (e) 119.4 [+ or -] 3.7
[AUC.sub.0-24h] 10.58 [+ or -]
 ([micro]g h/ml) 1.01 ([dagger],[double dagger])
([AUC.sub.0-24h]%) (e) 135.4 [+ or -] 6.4

Each value represents the mean[+ or -]S.E. (n = 5).
(a) SGT was administered alone at a single dose of 322.5 mg/kg
(control).
(b) SGT was administered as a single dose 5 h after the Pico
pretreatment.
(c) SGT was administered as a single dose 2 days after the Pico
pretreatment.
(d) SGT was administered repeatedly (twice a day at total daily dose of
645 mg/kg).
(e) Percentage relative to control group parameters.
*p < 0.01 vs. control value.
([dagger]) p < 0.01 vs. SGT administered 5h after Pico pretreatment.
([double dagger]) p < 0.01 vs. SGT administered 2 days after Pico
pretreatment.
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Author:He, Ju-Xiu; Goto, Emi; Akao, Teruaki; Tani, Tadato
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Geographic Code:9JAPA
Date:Aug 1, 2007
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