Changes in the Dissolution of Tolbutamide by a Traditional Chinese Medicine, Sho-Saiko-To (Xiao Chaihu Tang)

April 2001 Biol. Pharm. Bull. 24(4) 409—413 (2001) 409

Changes in the Dissolution of Tolbutamide by a Traditional Chinese Medicine, Sho-saiko-to (Xiao Chaihu Tang)

Nobuhiro NISHIMURA, Kohji NAORA, Hidenari HIRANO, and Kikuo IWAMOTO* Department of Pharmacy, Shimane Medical University Hospital, 89–1 Enya-cho, Izumo, Shimane 693–8501, Japan. Received October 30, 2000; accepted January 5, 2001

Dissolution rate is considered an important factor affecting absorption and efﬁcacy after the oral administration of tolbutamide. Since in many cases traditional Chinese medicines, including Sho-saiko-to (TJ-9, Xiao Chaihu Tang), are taken with other drugs, it is likely that the dissolution and absorption of concomitant drugs in the gastrointestinal tract are inﬂuenced by the presence of traditional Chinese medicines. In this study, the effects of TJ-9 on the in vitro dissolution of tolbutamide were examined. We carried out the dissolution test of tolbutamide in the absence or presence of traditional Chinese medicines (Kakkon-to, TJ-1; Hachimi-jio-gan, TJ-7; Chorei-to, TJ-40; Shakuyaku-kanzo-to, TJ-68; TJ-9; Gly- cyrrhizae Radix, GR; glycyrrhizin, GL) by using a pH 1.2 dissolution medium. Tolbutamide was determined by HPLC assay. The moment parameters, i.e., mean dissolution time (MDT), and the dissolution rate constant up to

20 min (kd) were estimated from the dissolution profiles on the basis of the first-order kinetics. Preparations containing GR, namely TJ-1, TJ-9 and TJ-68, significantly reduced the kd and increased the MDT of tolbutamide, while TJ-7 and TJ-40 had no effect on the early dissolution profile of tolbutamide. The ex-

tent of decrease in the kd in the presence of TJ-1, TJ-9 and TJ-68 was dependent on their GR contents. Similar inhibitory effects on the dissolution rate of tolbutamide were observed when GR alone was added to the test

medium. In addition, GL, a major constituent of GR, induced a 50% increase in MDT and a 30% decrease in kd. The above results indicate that Chinese traditional preparations containing GR have an inhibitory effect on the in vitro dissolution of tolbutamide, which is derived from GL in the preparations. Key words Sho-saiko-to; tolbutamide; dissolution; glycyrrhizin; Chinese medicine

Tolbutamide is classified into sulfonylureas prescribed for preparations. The effects of TJ-9 and its constituents on the the treatment of diabetic patients. The sulfonylureas have a in vitro dissolution of tolbutamide were examined. potent hypoglycemic effect and sometimes show delayed and erratic absorption, leading to unexpected hypoglycemia.1—3) MATERIALS AND METHODS Simons et al. reported that absorption patterns of tolbutamide were well correlated to the dissolution rate from the Materials The reagent of tolbutamide was obtained tablet.4) Although the rate of drug absorption is often not im- from Sigma Chemical Co. (St. Louis, MO, U.S.A.). Tolbu- portant in chronic therapy, some studies have suggested that tamide tablets (Rastinon®) and five traditional Chinese prepa- the absorption kinetics of tolbutamide may determine its hy- rations, Kakkon-to (TJ-1), Hachimi-jio-gan (TJ-7), Sho- poglycemic efficacy. Kivistö and Neuvonen demonstrated an saiko-to (TJ-9), Chorei-to (TJ-40), Shakuyaku-kanzo-to (TJ- increased absorption of tolbutamide with an enhancement of 68), were purchased from Aventis Pharma, Ltd. (Tokyo, blood glucose-lowering effects, presumably due to the im- Japan) and Tsumura & Co., Ltd. (Tokyo, Japan), respectively. proved dissolution of this sulfonylurea by the increase in gas- The TJ-9 extract, which was an extract from the mixture of tric pH.5) Additionally, it was reported that an increase in the herbal medicines composing TJ-9, and Glycyrrhizae Radix in vitro dissolution rate of tolbutamide tablets induced an in- (GR) extract, which includes Glycyrrhizic acid (glycyrrhizin, crease in absorption rates of tolbutamide and a decline in GL), were kindly gifted from Tsumura & Co., Ltd. The con- blood sugar levels in the early period after drug administra- tent of GL in GR was 12.4% (determined by Tsumura & Co., tion.6) Thus, the dissolution rate is considered an important Ltd.). The traditional Chinese preparations of TJ-1, TJ-7, TJ- factor affecting absorption and efficacy after the oral admin- 9, TJ-40 and TJ-68 were oral dosage preparations which in- istration of tolbutamide. cluded additives prescribed for therapeutic use. Herbal com- As the therapeutic use of traditional Chinese medicines positions of these five preparations are summarized in Table combined with other synthetic or biotechnological drugs has 1. GL was obtained from Tokyo Kasei Kogyo Co., Ltd. been increasing in Japan, serious adverse effects or drug in- (Tokyo, Japan). All other reagents and solvents were of ana- teractions caused by them have recently been reported.7—9) lytical grade. Sho-saiko-to (TJ-9; Xiao Chaihu Tang) is a major traditional Dissolution Test Dissolution tests of tolbutamide were Chinese medicine consisting of seven herbals, a mixture of performed in accordance with the Japanese Pharmacopoeia several crude drugs containing many natural substances. (JP) XIII dissolution test with paddle methods (100 rpm) for Since in many cases traditional Chinese medicines are taken tolbutamide tablet, with minor modifications. The JP XIII with other drugs, it is likely that the dissolution and absorp- disintegration medium No. 1 (pH 1.2) was used as the disso- tion of concomitant drugs in the gastrointestinal tract is influ- lution medium maintained at 37 °C in a water bath incubator. enced by the presence of traditional Chinese medicines. In the test using the tolbutamide reagent, tolbutamide was In this study, we employed TJ-9 as a traditional Chinese suspended at a concentration of 50 mg/ml in a 1% potato- medicine, since TJ-9 is one of the most commonly prescribed starch/0.9% NaCl solution. The test medium was pre-incu-

Table 1. Herbal Composition of Chinese Traditional Preparations represented as the Cs. In a preliminary study, we conﬁrmed

a) that tolbutamide concentrations in the medium with or with- Content (%) out TJ-9 did not change at all during 5 to 12 h after the be- Components TJ-1 TJ-7 TJ-9 TJ-40 TJ-68 ginning of the incubation, so that Cs was defined as the concentration of tolbutamide at 5 h. Aconiti Tuber 1.1 Measurement of Surface Tension After incubation of Alismatis Rhizoma 7.4 6.7 tolbutamide reagent (25 mg) with or without TJ-9 prepara- Asini Corii Collas 6.7 Bupleuri Radix 17.5 tion (125 mg) or GL (5.0 mg) in test medium (45 ml) for 30 Cinnamoni Cortex 5.6 2.6 min at 37 °C, the surface tension of each medium was mea- Corni Fructus 7.4 sured by the ring method using a Du Noüy tensiometer (DN; Dioscoreae Rhizoma 7.4 Shimadzu, Kyoto, Japan). Ephedrae Herba 8.3 Data Analysis The concentration of tolbutamide at infi- Glycyrrhizae Radix 5.6 5.0 16.7 Ginseng Radix 7.5 nite time (C∞) and the mean in vitro dissolution time (MDT) Hoelen 7.4 6.7 were defined as follows:

Moutan Cortex 5.8 ∞  dC  Paeoniae Radix 5.6 16.7 ϭ t C∞ ∫   dt (1) Pinelliae Tuber 12.5 0  dt  Polyporus 6.7 Puerariae Radix 11.1 ∞  dC  Rehmanniae Radix 14.4 ϭ t MDT ∫ t  dt/ C∞ (2) Scutellariae Radix 7.5 0  dt  Talcum Crystallinum 6.7 Zingiberis Rhizoma 5.6 2.5 where Ct is the concentration of tolbutamide dissolved in the Zizyphi Fructus 8.3 7.5 test medium at time t and dC /dt is the velocity of the tolbu- Additives 50.0 46.6 40.0 66.7 66.7 t tamide dissolution. The MDT was defined as the first mo- 10,11) a) Each value represents the blend ratio (% of the Chinese preparation) estimated ment of the dissolution rate-time curves of tolbutamide. from the labeled data (represented by Tsumura & Co., Ltd.). These moment parameters were calculated by trapezoidal in- tegration using a computer program (Maikon Ni Yoru bated with the TJ-9 preparation (1.67 g) or extract (0.1—1.0 Yakubutsu Sokudoron Nyumon; Nanzando, Tokyo, Japan). g) for 30 min. Five milliliters of the tolbutamide suspension The dissolution rate constant for tolbutamide, kd, was cal- were transferred into 500 ml of the dissolution medium to culated from C∞ and first-order kinetics of the dissolution start the dissolution test. In the tablet test, a tolbutamide profile of tolbutamide up to 20 min after the beginning of the tablet (500 mg) was placed into 900 ml of the dissolution test by the following equation: medium, which was pre-incubated with or without traditional dCt ϭϪkC()∞ C (3) Chinese preparations (2.5 g) or GR (0.05—0.25 g) or GL dt d t (0.01, 0.05 g) for 30 min. In both tests, 1 ml of dissolution medium was collected periodically after the beginning of the Assay Tolbutamide concentrations in the medium were test. Collected medium was immediately filtered through a determined by a HPLC method in accordance with our previ- 0.45 mm membrane (Chromatodisk: Kurabo Industries, Ltd., ous report.12) Briefly, filtered dissolution medium (50 ml) was Osaka, Japan), and then the filtrate was used for the determi- added to 100 ml of the internal standard solution (50 mg/ml of nation of tolbutamide. Additionally, the pH of the medium chlorpropamide) and 350 ml of an acetonitrile–water mixture was determined periodically using a compact pH meter with (1 : 1), and then shaken for 1 min. After centrifugation at combined electrode (B-212; Horiba Seisakusho, Ltd., Kyoto, 10000 rpm for 5 min, 10 ml of the supernatant was injected Japan). into the chromatograph. Stability Test The dissolution medium (pH 1.2) contain- Statistics Significance of difference was determined by ing tolbutamide (completely dissolved; 100 mg/ml, 900 ml) Student’s t-test or one-way analysis of variance (one-way was incubated in the absence or presence of TJ-9 preparation ANOVA). In all cases, a p value of 0.05 or less was consid- (2.5 g), TJ-68 preparation (2.5 g), GR (0.5 g) or GL (0.05 g) ered to be statistically significant. in accordance with the dissolution test. The medium (1 ml) was collected and filtered with a 0.45 mm membrane periodi- RESULTS cally up to 60 min to determine the concentrations of tolbutamide. Effects of TJ-9 on Tolbutamide Reagent Dissolution

Saturated Concentration (Cs) of Tolbutamide Tolbu- Figure 1 shows the dissolution profiles of tolbutamide in a tamide reagent (25 mg) was vigorously shaken in 45 ml of medium (pH 1.2) in the absence or presence of TJ-9. In this the test medium (pH 1.2) for 5 h using a water bath incubator experiment, the pure reagent (powder) of tolbutamide was (37 °C) in the absence or presence of Chinese medicines. used. Tolbutamide concentrations in the medium were low- The preparations of TJ-1, TJ-7, TJ-9, TJ-40 and TJ-68 (125 ered by the presence of the TJ-9 extract depending on the mg), TJ-9 extract (75 mg), GR (2.5—12.5 mg) and GL added amount of tolbutamide. TJ-9 preparation also lowered (0.5—5.0 mg) were used as Chinese medicines and their tolbutamide levels in the medium to the same extent. The components. After incubation, the medium was collected and dissolution parameters are summarized in Table 2. MDT of filtered to determine the concentration of tolbutamide. The tolbutamide in the presence of TJ-9 preparation and extract concentrations of tolbutamide obtained in the medium were was significantly prolonged to about 3—4-fold that of the April 2001 411

Fig. 1. Dissolution Proﬁles of Tolbutamide from Powder (Tolbutamide Fig. 2. Correlation between the GR Content in Traditional Chinese Prepa- Reagent, 250 mg) in a Dissolution Medium (pH 1.2, 500 ml) in the Absence rations (᭿, Control; ᭡, TJ-1; ᮀ, TJ-7; ᭹, TJ-9; ᭝, TJ-40; ᭺, TJ-68) and (᭡) or Presence of TJ-9 Preparation (᭹, 1.67 g) or TJ-9 Extract (᭝, 0.1 g; Log kd of Tolbutamide in the Dissolution Medium (pH 1.2, 900 ml)

᭺, 0.5 g; ᭿, 1.0 g) Each point represents the mean and S.D. of 3 experiments. The kd is the early disso- Each point represents the mean and S.D. of 3 experiments. lution rate constant for tolbutamide tablets (500 mg) up to 20 min during the dissolution test. GR contents are expressed as a blend ratio (% of Chinese preparation).

Table 2. Dissolution Parameters of Tolbutamide in Dissolution Medium (pH 1.2, 500 ml) with or without TJ-9 Preparation or Extract after the Trans- fer of Tolbutamide Reagent (250 mg)

Ϫ1 MDT (min) kd (min )

Control 3.19Ϯ1.31 0.2307Ϯ0.1283 TJ-9 preparation (g/500 ml) 1.67 10.17Ϯ1.87* 0.0706Ϯ0.0088* TJ-9 extract (g/500 ml) 0.1 8.39Ϯ1.33* 0.0902Ϯ0.0102* 0.5 10.71Ϯ3.83* 0.0890Ϯ0.0161* 1.0 12.33Ϯ2.87** 0.0777Ϯ0.0056*

Each value represents the meanϮS.D. of three experiments. ∗ pϽ0.05, ∗∗ pϽ0.01, Fig. 3. Effects of GR (Panel A: ᭿, Control; ᭝, 0.05 g; ᭡, 0.10 g; ᭺, 0.25 significant difference from the control (ANOVA). MDT was the mean dissolution time g) or GL (Panel B: ᭿, Control; ᮀ, 0.01 g; ᭹, 0.05 g) on the Dissolution Pro- for the tolbutamide reagent, and kd was the dissolution rate constant up to 20 min dur- files of Tolbutamide Tablet (500 mg) in Dissolution Medium (pH 1.2, 900 ing the dissolution test. ml) Each point represents the mean and S.D. of 3 experiments. Table 3. Dissolution Parameters of Tolbutamide in Dissolution Medium (pH 1.2, 900 ml) with or without Traditional Chinese Medicines (2.5 g) after Addition of Tolbutamide Tablet (500 mg) fect on the dissolution parameters of tolbutamide. TJ-1, TJ-9 Ϫ1 and TJ-68 contain GR as only the common component, MDT (min) kd (min ) Cs (mg/ml) whereas GR is not contained in TJ-7 and TJ-40. Therefore, kd Control 23.0Ϯ2.4 0.0513Ϯ0.0019 127.9Ϯ0.8 values were plotted against GR contents in the preparations TJ-1 30.3Ϯ5.0 0.0383Ϯ0.0026** 140.0Ϯ1.0** (Fig. 2). The log k was significantly decreased by TJ-1, TJ-9 TJ-7 24.6Ϯ1.7 0.0457Ϯ0.0022 135.4Ϯ3.3** d Ϯ Ϯ Ϯ and TJ-68 depending on their GR contents, and a significant TJ-9 42.2 4.7** 0.0354 0.0004** 145.4 2.4** ϭ Ͻ TJ-40 23.6Ϯ0.5 0.0523Ϯ0.0052 135.6Ϯ2.2** correlation (r 0.881, p 0.001) between the log kd and GR TJ-68 45.9Ϯ0.5** 0.0299Ϯ0.0032** 123.4Ϯ0.7 content was observed. Effects of GR and GL on Tolbutamide Dissolution Each value represents the meanϮS.D. of three experiments. ∗ pϽ0.05, ∗∗ pϽ0.01, significant difference from the control (ANOVA). MDT was the mean dissolution time Figure 3 and Table 4 show the changes in concentration–time for tolbutamide tablet, kd was the dissolution rate constant up to 20 min during the dis- courses and dissolution parameters of tolbutamide when GR solution test, and C was the saturated concentration of tolbutamide. s or GL has been added to the medium. GR significantly reduced the tolbutamide concentrations over the dissolution control. The kd was reduced to about 40% of the control by test in every amount added to the medium. Also, a 30— the TJ-9 preparation and extract. This inhibitory effect of the 100% increase in the MDT and a 15—40% decrease in the kd TJ-9 extract on the dissolution rate of tolbutamide was de- were observed in the presence of GR. Furthermore, the addi- pendent on the added concentration in the test medium. tion of GR reduced the Cs to about 65—85% of the control. Effects of Traditional Chinese Preparations on Tolbu- These effects on the dissolution parameters of tolbutamide by tamide Tablet Dissolution The effects of various Chinese the addition of GR were concentration-dependent. Similar medicines, including TJ-9, on tolbutamide dissolution from changes in dissolution profiles and parameters of tolbutamide the commercial tablet formulation were examined. Dissolu- were found when GL, a major constituent of GR, was added tion parameters are shown in Table 3. The kd and MDT were to the medium. In the test medium containing GL, concentra- significantly decreased and increased by the addition of TJ-1, tion-dependent, significant decreases in kd and Cs and prolon- TJ-9 and TJ-68. In contrast, TJ-7 and TJ-40 induced no ef- gation of MDT were observed. 412 Vol. 24, No. 4

Table 4. Dissolution Parameters of Tolbutamide in Dissolution Medium TJ-9 has an inhibitory effect on the dissolution of tolbu- (pH 1.2, 900 ml) with or without GR or GL tamide in a pH 1.2 medium. MDT (min) k (minϪ1) C (mg/ml) In the dissolution experiments, both of a reagent (Fig. 1, d s Table 2) and tablet (Table 3) were used as tolbutamide for- Control 23.0Ϯ2.4 0.0513Ϯ0.0019 127.9Ϯ0.8 mulations. The process of disintegration is not included in GR (g/900 ml) the dissolution from the reagent (powder) but from the tablet. Ϯ Ϯ Ϯ 0.05 30.0 0.5** 0.0425 0.0013** 109.0 0.6* The mean disintegration time (MDIT) can be calculated by 0.10 40.7Ϯ4.9** 0.0341Ϯ0.0050** 99.9Ϯ1.3** 0.25 46.7Ϯ5.4** 0.0304Ϯ0.0063** 94.6Ϯ0.5** following equation: GL (g/900 ml) MDT ϭMDITϩMDT (4) 0.01 31.7Ϯ2.3 0.0388Ϯ0.0010** 128.9Ϯ0.5 tablet powder 0.05 36.1Ϯ6.5** 0.0370Ϯ0.0013** 81.2Ϯ2.7** where MDTtablet and MDTpowder were the MDTs for tolbu- Each value represents the meanϮS.D. of three experiments. MDT was the mean dis- tamide tablet and reagent (powder), respectively. Calculated solution time for tolbutamide tablet, Cs was the saturated concentration of tolbutamide, MDITs for the control were 19.8 min, which increased to and k was the dissolution rate constant up to 20 min during the dissolution test. d 32.0 min by the addition of TJ-9. This indicates that TJ-9 has ∗ pϽ0.05, ∗∗ pϽ0.01, signiﬁcant difference from the control (ANOVA). an effect on both the disintegration and dissolution processes. In order to determine the crude component(s) which may Medium pH The dissolution medium with no Chinese be responsible for an inhibitory effect on the dissolution of medicines had pH values of 1.20Ϯ0.02 throughout the disso- tolbutamide, we examined the effects of ﬁve traditional Chi- lution test. No change was observed in the pH value (1.19Ϯ nese preparations, TJ-1, TJ-7, TJ-9, TJ-40 and TJ-68, which 0.03) by the addition of Chinese medicines, GR or GL. are formulated with various compositions of herbs (Table 1),

Surface Tension of the Medium The surface tension of on the dissolution of tolbutamide from a tablet. The kd was the test medium including tolbutamide alone was 72.4Ϯ1.2 significantly reduced by the presence of TJ-1, TJ-9 and TJ- mN/m. The presence of TJ-9 and GL with tolbutamide sig- 68, which contained GR as the only common component. In nificantly reduced the surface tension of the medium to contrast, those Chinese medicines without GR, TJ-7 and TJ- 49.4Ϯ2.3 and 52.8Ϯ2.5 mN/m, respectively (pϽ0.001, both 40, did not have any effect on tolbutamide dissolution. In ad- of TJ-9 and GL). However, no difference in effect on the sur- dition, a significant relationship was observed between the face tension was observed between TJ-9 and GL. GR content and log kd in TJ-1, TJ-9 and TJ-68. From these Stability of Tolbutamide The concentrations of tolbu- results, it is suggested that the constituent herb GR caused tamide in the dissolution medium of pH 1.2 were within the inhibitory effect of TJ-9 on the dissolution of tolbu- 98.7—103.0% of the initial concentration until 60 min. The tamide. To confirm this supposition, the effect of plain GR stability of tolbutamide in the solution was not changed in extract on the dissolution of tolbutamide tablet was investi- the presence of TJ-9, TJ-68, GR or GL. gated. As expected, GR reduced the dissolution rate of tolbutamide in a concentration-dependent manner. Furthermore, DISCUSSION similar changes in dissolution profiles and the dissolution parameters of tolbutamide were induced by GL, a major and ef- In general, the dissolution of drugs is the first process of ficacious constituent of GR. These findings indicate that the absorption in the gastrointestinal tract after oral administra- inhibition of tolbutamide dissolution in the early period in- tion. Tolbutamide is a weakly acidic compound with a pKa of duced by TJ-9 could be ascribed to GR, and that GL may 5.3, which indicates low aqueous solubility at an acidic pH. mainly contribute to this effect of GR. However, tolbutamide can be absorbed in the stomach,13) so Several possible mechanisms for the changes in tolbu- that intragastric dissolution may influence the initial absorp- tamide dissolution kinetics caused by the Chinese medicines, tion of tolbutamide after oral administration. In this study, GR and GL can be considered. The pH values of the medium therefore, in vitro dissolution kinetics of tolbutamide were remained constant even when Chinese medicines, GR and investigated at the gastric pH, 1.2. Early dissolution profiles GL were added. The stability studies for 1 h showed that of tolbutamide were evaluated with a dissolution rate con- tolbutamide could not be degraded in an acidic medium (pH stant up to 20 min, kd. We also evaluated the dissolution ki- 1.2), and that neither TJ-9, TJ-68, GR nor GL affected the netics of tolbutamide using the moment parameter, mean dis- stability of tolbutamide in the solution. In addition, tolbu- solution time (MDT). The solubility of tolbutamide was di- tamide was stable for at least 12 h in the medium with or rectly measured as the saturated concentration (Cs). The ef- without TJ-9, as demonstrated in the preliminary study of Cs fects of traditional Chinese medicines, GR and GL on the in determination. The results of these pH and stability tests in- vitro dissolution of tolbutamide were evaluated by these dis- dicate that Chinese medicines, GR and GL influenced the solution parameters, kd, MDT and Cs. dissolution rate and solubility of tolbutamide by factors other At first, the effects of TJ-9 on tolbutamide dissolution than medium pH or degradation. were examined. Since commercially available TJ-9 granule is Itai et al. reported that a surfactant, polysorbate 80, in- prepared with additive ingredients, we also compared the ef- creased the saturated concentration of flufenamic acid by mi- fects of TJ-9 preparation with those of TJ-9 extract without celle solubilization and decreased the dissolution rate con- any ingredients. As shown in Fig. 1 and Table 2, kd and MDT stant, presumably due to a lowering of the diffusion rate re- were decreased and increased by the addition of TJ-9 prepa- sulting from micelle formation.14) GL is known to be a nat- ration, respectively, and the same results were observed with ural surfactant with surface-active properties which can TJ-9 extract (1.0 g) as well. In addition, TJ-9 extract showed change the solubility of various substances by micelle forma- a concentration-dependent effect. These results indicate that tion.15,16) It is likely that TJ-9, which contains GL, works as a April 2001 413 surfactant in the solution as well. In this experiment, the sur- lution rates of tolbutamide by Chinese medicines were due to face tension of the solution was reduced by the addition of GL, a major component of GR. TJ-9 and GL to the same extent. Since the surface tension is one of the indicators of micelle formation, TJ-9 and GL are Acknowledgment The authors are grateful to Prof. M. considered to change the kd and Cs of tolbutamide by their Yamamoto of Fukuoka University for technical support on surface-active effects. the measurement of surface tension.

However, the reason Cs values of tolbutamide decreased when GR and GL were added to the medium is uncertain. It REFERENCE has been reported that GL was electrically adsorbed onto the suspended particle of sulfathiazole17) which had a chemical 1) Wåhlin-Boll E., Melander A., Sartor G., Schersten B., Eur. J. Clin. structure similar to tolbutamide. A possible electrical interac- Pharmacol., 18, 279—283 (1980). 2) Ikegami H., Shima K., Tanaka A., Tahara Y., Hirota M., Kumahara Y., tion between GL and suspended tolbutamide particles may Acta Endocrinol., 111, 528—532 (1986). affect the dissolution characteristics. There is a possibility 3) Kradjan W. A., Konayasi K. A., Bauer L. A., Horn J. R., Opheim K. that crude components other than GL are involved in the in- E., Wood F. J., J. Clin. Pharmacol., 29, 1121—1127 (1989). 4) Simmons D. L., Legpre A. A., Picotte P., Lee K. S., J. Pharmacokin. creased Cs by Chinese medicines, because TJ-7 and TJ-40 increased the C (Table 3) even though these preparations did Biopharm., 3, 39—49 (1975). s 5) Kivistö K. T., Neuvonen P. J., Eur. J. Clin. Pharmacol., 42, 675—680 not include GL. In fact, it is known that the Chinese prepara- (1992). tions used in this study contain many kinds of saponins 6) Nelson E., Knoechel E. L., Hamlin W. E., Wagnaer J. G., J. Pharm. which are known to have surface-active properties. Sci., 51, 509—514 (1962). Previously, we reported that the co-administration of TJ-9 7) Miller L. G., Arch. Intern. Med., 158, 2200—2211 (1998). reduced the bioavailability of tolbutamide after oral adminis- 8) Ishizaki T., Sasaki F., Ameshima S., Shiozaki K., Takahashi H., Abe 18) Y., Ito S., Kuriyama M., Nakai T., Kitagawa M., Eur. Respir. J., 9, tration in rats. In general, the reduced dissolution rate of 2691—2696 (1996). the drugs tends to reduce their bioavailability, so that the in- 9) Page R. L., Lawrence J. D., Pharmacotherapy, 19, 870—876 (1999). hibitory effects of TJ-9 on the dissolution rate of tolbutamide 10) Tanigawara Y., Yamaoka K., Nakagawa T., Uno T., J. Pharm. Sci., 71, may be one of the possible mechanisms for the reduced 1129—1133 (1982). 11) Tanigawara Y., Yamaoka K., Nakagawa T., Uno T., Chem. Pharm. bioavailability of tolbutamide. In contrast, it was also demon- Bull., 30, 1088—1090 (1982). strated that TJ-9 showed an enhancing effect on the initial ab- 12) Nishimura N., Naora K., Hirano H., Iwamoto K., J. Pharm. sorption rate of tolbutamide after oral administration.12,18) Pharmacol., 50, 231—236 (1998). The results of the present studies indicate that the reason for 13) Miller W. L., Krake J. J., Vander Brook M. J., Reineke L. M., Ann. N. the accelerated absorption of tolbutamide from the gastroin- Y. Acad. Sci., 71, 118—124 (1957). 14) Itai S., Nemoto M., Kouchiwa S., Murayama H., Nagai T., Chem. testinal tract does not lie in the dissolution process of this Pharm. Bull., 33, 5464—5473 (1985). drug. It might be induced by other factors, such as a change 15) Otsuka A., Yonezawa Y., Iba K., Tatsumi T., Sunada H., Yakugaku in drug transport through the intestinal membrane. Zasshi, 96, 203—208 (1976). From the present study, it is concluded that TJ-9 reduced 16) Yonezawa Y., Otsuka A., Yakugaku Zasshi, 101, 829—835 (1981). the early dissolution rate of tolbutamide from the tablet and 17) Otsuka A., Yonezawa Y., Nakamura Y., J. Pharm. Sci., 67, 151—154 (1978). reagent at the gastric pH 1.2. In addition, other traditional 18) Nishimura N., Naora K., Hirano H., Iwamoto K., Am. J. Chin. Med., Chinese preparations, TJ-1 and TJ-68, containing GR had the 27, 355—363 (1999). same inhibitory effect as TJ-9. Furthermore, decreased disso-