Tegaserod Research Articles

Integrated transcriptomics- and structure-based drug repositioning identifies drugs with proteasome inhibitor properties

Computational pharmacogenomics can potentially identify new indications for already approved drugs and pinpoint compounds with similar mechanism-of-action. Here, we used an integrated drug repositioning approach based on transcriptomics data and structure-based virtual screening to identify compounds with gene signatures similar to three known proteasome inhibitors (PIs; bortezomib, MG-132, and MLN-2238). In vitro validation of candidate compounds was then performed to assess proteasomal proteolytic activity, accumulation of ubiquitinated proteins, cell viability, and drug-induced expression in A375 melanoma and MCF7 breast cancer cells. Using this approach, we identified six compounds with PI properties ((-)-kinetin-riboside, manumycin-A, puromycin dihydrochloride, resistomycin, tegaserod maleate, and thapsigargin). Although the docking scores pinpointed their ability to bind to the β5 subunit, our in vitro study revealed that these compounds inhibited the β1, β2, and β5 catalytic sites to some extent. As shown with bortezomib, only manumycin-A, puromycin dihydrochloride, and tegaserod maleate resulted in excessive accumulation of ubiquitinated proteins and elevated HMOX1 expression. Taken together, our integrated drug repositioning approach and subsequent in vitro validation studies identified six compounds demonstrating properties similar to proteasome inhibitors.

Tegaserod maleate exhibits antileukemic activity by targeting TRPM8

To identify therapeutic targets in acute myeloid leukemia (AML), we conducted growth inhibition screens of 2040 small molecules from a library of FDA-approved drugs using a panel of 12 AML cell lines. Tegaserod maleate, a 5-hydroxytryptamine 4 receptor partial agonist, elicits strong anti-AML effects in vitro and in vivo by targeting transient receptor potential melastatin subtype 8 (TRPM8), which plays critical roles in several important processes. However, the role of TRPM8 remains incompletely described in AML, whose treatment is based mostly on antimitotic chemotherapy. Here, we report an unexpected role of TRPM8 in leukemogenesis. Strikingly, TRPM8 knockout inhibits AML cell survival/proliferation by promoting apoptosis. Mechanistically, TRPM8 exerts its oncogenic effect by regulating the ERK–CREB/c-Fos signaling axis. Hyperactivation of ERK signaling can be reversed by TRPM8 inhibition. Importantly, TRPM8 is overexpressed in AML patients, indicating that it is a new prognostic factor in AML. Collectively, our work demonstrates the anti-AML effects of tegaserod maleate via targeting TRPM8 and indicates that TRPM8 is a regulator of leukemogenesis with therapeutic potential in AML.

Tegaserod Maleate Suppresses the Growth of Gastric Cancer In Vivo and In Vitro by Targeting MEK1/2.

Simple SummaryThe MAP kinase cascades are the most important oncogenic drivers of human cancers, including gastric cancer, and blocking this pathway with targeted inhibitors is an important antitumor strategy. Tegaserod maleate binds to MEK1 and MEK2, inhibiting kinase activity and thus suppressing the MEK1/2-ERK1/2 signaling pathway. Thus, tegaserod maleate may have potential as a MEK1/2 inhibitor for gastric cancer.Gastric cancer (GC) ranks fifth in global incidence and fourth in mortality. The current treatments for GC include surgery, chemotherapy and radiotherapy. Although treatment strategies for GC have been improved over the last decade, the overall five-year survival rate remains less than 30%. Therefore, there is an urgent need to find novel therapeutic or preventive strategies to increase GC patient survival rates. In the current study, we found that tegaserod maleate, an FDA-approved drug, inhibited the proliferation of gastric cancer cells, bound to MEK1/2 and suppressed MEK1/2 kinase activity. Moreover, tegaserod maleate inhibited the progress of gastric cancer by depending on MEK1/2. Notably, we found that tegaserod maleate suppressed tumor growth in the patient-derived gastric xenograft (PDX) model. We further compared the effect between tegaserod maleate and trametinib, which is a clinical MEK1/2 inhibitor, and confirmed that tegaserod maleate has the same effect as trametinib in inhibiting the growth of GC. Our findings suggest that tegaserod maleate inhibited GC proliferation by targeting MEK1/2.

Tegaserod Maleate Inhibits Breast Cancer Progression and Enhances the Sensitivity of Immunotherapy.

Background Breast cancer (BC) is the most commonly diagnosed cancer in women worldwide. The challenge in managing this heterogeneous malignancy is that BC is highly aggressive and is always associated with chemical resistance, radiation resistance, hormone therapy resistance, and targeted therapy resistance. Therefore, there is an urgent need to find effective drugs to treat BC. Methods Based on the Selleck drug library approved by FDA, we screened 800 drugs for anti-BC cells and found that tegaserod maleate (TM), a 5-hydroxytryptamine 4-receptor (HTR4) partial agonist had the best anti-BC effect, which was further verified. The effects of different concentrations of TM on cell proliferation, invasion, and migration were evaluated in vitro using CCK8, plate cloning, transwell, and scratch assays. The UALCAN database, Kaplan–Meier Plotter database, Human Protein Atlas, and GEPIA2 were used to explore the correlation between HTR4 expression and BC patients' clinicopathological data as well as immune response. In vivo experiments demonstrated the effect of the TM and immunotherapy drug (anti-PD1/anti-TIGIT) combination on BC tumor growth in mice. Results TM significantly inhibited the proliferation, invasion, and migration of BC cells, and the higher the concentration, the better the inhibition effect. HTR4 was significantly downregulated in BC tissues compared to paracancerous tissues. The downregulation of HTR4 was correlated with clinicopathological data and positively correlated with BC prognosis. Interestingly, the GEPIA2 database suggested that there was a strong positive correlation between the expression of HTR4 and effector T cells, effector memory T cells, and exhausted T cells. In vitro experiments showed that TM, anti-PD1, and anti-TIGIT could all inhibit the growth and weight of BC tumors as compared with the control group. However, when anti-PD1 or anti-TIGIT was used simultaneously with TM, the inhibition of tumors significantly exceeded that in the control group. Moreover, the combination of anti-TIGIT and TM has the best inhibitory effect. Conclusion TM inhibited the progression of breast cancer, and its combination with anti-TIGIT could effectively inhibit tumor growth and improve the sensitivity of immunotherapy in breast cancer.

Tegaserod Maleate Inhibits Esophageal Squamous Cell Carcinoma Proliferation by Suppressing the Peroxisome Pathway.

Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are the two major types of esophageal cancer (EC). ESCC accounts for 90% of EC. Recurrence after primary treatment is the main reason for poor survival. Therefore, recurrence prevention is a promising strategy for extending the 5-year survival rate. Here, we found tegaserod maleate could inhibit ESCC proliferation both in vivo and in vitro. Proteomics analysis revealed that tegaserod maleate suppressed the peroxisome signaling pathway, in which the key molecules peroxisome membrane protein 11B (PEX11B) and peroxisome membrane protein 13 (PEX13) were downregulated. The immunofluorescence, catalase activity assay, and reactive oxygen species (ROS) confirmed that downregulation of these proteins was related to impaired peroxisome function. Furthermore, we found that PEX11B and PEX13 were highly expressed in ESCC, and knockout of PEX11B and PEX13 further demonstrated the antitumor effect of tegaserod maleate. Importantly, tegaserod maleate repressed ESCC tumor growth in a patient-derived xenograft (PDX) model in vivo. Our findings conclusively demonstrated that tegaserod maleate inhibits the proliferation of ESCC by suppressing the peroxisome pathway.

Early Intervention and Resolution of Pediatric Intestinal Pseudo-Obstruction in Systemic Lupus Erythematosus: A Pediatric Case Report

Early Intervention and Resolution of Pediatric Intestinal Pseudo-Obstruction in Systemic Lupus Erythematosus: A Pediatric Case Report

Commentary: tegaserod and IBS, two decades on.

THIS IS A SPECIAL COMMENTARY ON “TEGASEROD, A 5‐HT4 RECEPTOR PARTIAL AGONIST, RELIEVES SYMPTOMS IN IRRITABLE BOWEL SYNDROME PATIENTS WITH ABDOMINAL PAIN, BLOATING AND CONSTIPATION” BY MÜLLER‐LISSNER, S.A., FUMAGALLI, I., BARDHAN, K.D., PACE, F., PECHER, E., NAULT, B., AND RÜEGG, P., ORIGINALLY PUBLISHED IN AP&T IN 2008. DOI:10.1046/J.1365-2036.2001.01094.x

Zelnorm, an agonist of 5-Hydroxytryptamine 4-receptor, acts as a potential antitumor drug by targeting JAK/STAT3 signaling.

The Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway plays central roles in cancer cell growth and survival. Drug repurposing strategies have provided a valuable approach for developing antitumor drugs. Zelnorm (tegaserod maleate) was originally designed as an agonist of 5-hydroxytryptamine 4 receptor (5-HT4R) and approved by the FDA for treating irritable bowel syndrome with constipation (IBS-C). Through the use of a high-throughput drug screening system, Zelnorm was identified as a JAK/STAT3 signaling inhibitor. Moreover, the inhibition of STAT3 phosphorylation by Zelnorm was independent of its original target 5-HT4R. Zelnorm could cause G1 cell cycle arrest, induce cell apoptosis and inhibit the growth of a variety of cancer cells. The present study identifies Zelnorm as a novel JAK/STAT3 signaling inhibitor and reveals a new clinical application of Zelnorm upon market reintroduction.

DESIGN AND EVALUATION OF COLON TARGETED DELIVERY OF TEGASEROD MALEATE FOR IRRITABLE BOWEL SYNDROME

The colon is being extensively investigated as a drug delivery site. Colonic drug delivery is a relatively recent approach for the treatment of diseases like ulcerative colitis, Crohn’s disease, and irritable bowel syndrome. To achieve successful colon targeted drug delivery, a drug needs to be protected from degradation, release and /or absorption in upper portion of GI tract and then ensure abrupt or controlled release in proximal colon. The purpose of this research is to develop and evaluate the polysaccharide based compression coated tablets of Tegaserod maleate for the treatment of irritable bowel syndrome. Core tablets of Tegaserod maleate were compression coated with various proportions of Galactosol, xanthan gum and chitosan. This work aimed to prepare compression coated tablets by direct compression method using single polymer and combination of polymers. And to evaluate prepared tablets parameters like hardness, friability, thickness, diameter, weight variation, drug content, swelling index, in vitro drug release. Keywords: Colon, Tegaserod maleate, Galactosol, xanthan gum and chitosanÂ

Visceral analgesic effect of 5-HT4 receptor agonist in rats involves the rostroventral medulla (RVM)

The 5-HT4 receptor agonist tegaserod (TEG) has been reported to modulate visceral pain. However, the underlying mechanism remains unknown. The objective of the present study was to examine the analgesic mechanism and site of action of TEG. In male rats, visceral pain was assessed by measuring visceromotor response (VMR) to colorectal distension (CRD). Inflammation was induced by intracolonic injection of tri-nitrobenzene sulfonic acid (TNBS). The effect of TEG on the VMR was tested by injecting intraperitoneal (i.p.), intrathecal (i.t.), intracerebroventricular (i.c.v) or in the rostroventral medulla (RVM). The effect of the drug was also tested on responses of CRD-sensitive pelvic nerve afferents (PNA) and lumbo-sacral (LS) spinal neurons. Systemic injection of TEG attenuated VMR in naive and TNBS-treated rats. Similarly, supraspinal, but not spinal, injection of TEG attenuated the VMR. While GR113808, (selective 5-HT4 antagonist) blocked the effect, naloxone (NLX) an opioid receptor antagonist reversed the effect of TEG. Although i.t. NLX did not block the inhibitory effect of TEG in VMR study, i.t. injection of α2-adrenergic receptor antagonist yohimbine blocked the effect of TEG when given systemically. While TEG had no effect on the responses of CRD-sensitive PNA, it inhibited the responses of CRD-sensitive LS neurons in spinal intact condition. This inhibition was blocked by GR113808, NLX and β-funaltrexamine (β-FNA) when injected into the RVM. Results indicate that TEG produces analgesia via activation of supraspinal 5-HT4 receptors which triggers the release of opioids at supraspinal site, which activates descending noradrenergic pathways to the spinal cord to produce analgesia.

Synthesis and Characterization of Process Related Impurities of Tegaserod Maleate

Synthesis and Characterization of Process Related Impurities of Tegaserod Maleate

W1729 Volume Dependent Recruitment of Adaptive Esophageal Peristaltic and Upper Esophageal Sphincter Contractile Reflexes Is Preserved in Sleep State in Healthy Premature Infants

Background: Serotonin (5-HT) plays a major role in gastrointestinal (GI) functions. Of several subtypes of 5-HT receptors, 5-HT3 and 5-HT4 are involved in GI motility and pain. 5-HT4 receptor agonist tegaserod (TEG) has been shown to modulate visceral pain in both humans and animals. However, its underlying mechanism of action remains unknown. Aim: The objective of the present study is to examine the site of action of this drug in colorectal distension (CRD)-induced visceral pain in naive and post-inflamed sensitized rats. Methods: In each of 47 male Sprague-Dawley rats under fully anesthetized state, a bipolar electrode was implanted surgically into the external oblique muscle of the abdomen to measure the visceromotor response (VMR) represented as electrical activity (EMG) of the muscle to graded CRD (10-80mmHg). VMR was recorded in fully awake rats 72 hours following the surgery. To induce colonic inflammation, 0.5ml of tri-nitrobenzene sulfonic acid (TNBS) in 50% ethanol was infused into the colon under the influence of anesthesia and rats were tested 7days after TNBS injection. Drugs were injected either intraperitoneally (ip), intravenously (iv) or subcutaneously (sc). Electrophysiological recordings were made from the S1 sacral dorsal root receiving pelvic nerve innervating the colon. Responses of pelvic afferents to CRD were recorded before and after TEG injection. Results: Rats exhibited linear increasing VMR to graded CRD. TNBS-treated rats exhibited significantly (p<0.05 vs naive) greater VMR suggesting the sensitization following inflammation. High doses of TEG (5 and 10mg/ kg, ip) resulted in severe CNS effect including agitation, motor impairment and sedation (n=4). CNS effects were delayed in atropine (5mg/kg, ip) pretreated rats (n=4). Lower doses (0.5 and 1mg/kg, ip) of TEG did not produce any visible CNS effect. TEG (1mg/kg) significantly attenuated VMR in both naive and post-inflamed rats. Atropine failed to block the effect of TEG, suggesting that visceral analgesia was not mediated via muscariniccholinergic system. Selective 5-HT4 antagonist GR113808 (5mg/kg, sc) significantly reversed the effect of TEG. Similarly, opioid receptor antagonist naloxone (5mg/kg, iv) significantly reversed the effect of TEG. In electrophysiology experiments, TEG (1mg/kg, ip) did not attenuate the mechanotransduction of colonic pelvic nerve afferents in either naive or postinflamed rats. Conclusion: Results suggest that TEG produces visceral analgesia via the activation of central 5-HT4 receptors. Since opioid antagonist naloxone blocks the effect of TEG, it suggests that the central opioidergic system is linked to 5-HT4 mediated visceral analgesia.

T1272 Muscarinic Antagonist Reduced Tegaserod-Induced Contractions of Fundus But Not Antrum in Obese Type 2 Diabetic But Not Control Mice

Prokinetic drugs accelerate gastric emptying in diabetic patients with gastroparesis. Tegaserod, a 5-HT4 partial agonist, increases GI motility by enhancing Ach release from autonomic neurons innervating smooth muscle. Autonomic neuropathy, evident in animal models of diabetes, may alter the efficacy of prokinetic drugs which rely on effective neuromuscular transmission to increase motility. These studies examined the effect of tegaserod on motility of whole thickness rings of fundus and antrum from control (KK) and obese type 2 diabetic Agouti mice (KK.Cg-Aγ) using tissue bath set-up. Tissues were pretreated with vehicle or 4-DAMP (M3 muscarinic receptor antagonist), then treated with bethanechol or tegaserod (TG). Drug responses were quantified as area under the curve (g*s) or peak contraction (g). At 7 weeks after diabetes onset, diabetic mice were heavier (42±1g) than control mice (32±1g). Bethanechol (10 μM)-induced peak contractions of antrum, but not fundus, were reduced in diabetic as compared to control mice [antrum: control (n=11), 1.6±0.2; diabetic (n=10), 1.1±0.1*; *p<0.05][fundus: control (n=9), 2.9±0.3; diabetic (n=11), 2.8±0.3]. In both control and diabetic mice, TG treatment resulted in relaxation of antrum [0.1 μM: control (n=13), 1±1; diabetic (n=12), 3±2] [1.0 μM: control (n=14), -1±1; diabetic (n=12), -1±3] [10 μM: control (n=14), -6±2; diabetic (n=15), -5±3], but contraction of fundus [0.1 μM: control (n=13), 10±3; diabetic (n=11), 6±4] [1.0 μM: control (n=13), 18±6; diabetic (n=11), 31±11] [10 μM: control (n=13), 28±10; diabetic (n=13), 43±13]. 4-DAMP at 0.5 μM was equally effective, but at 1 μM was more effective, in reducing bethanechol (10 μM)induced contractions of fundus from diabetic mice [vehicle: (n=11), 380±58; 0.5 μM: (n= 8), 77±23; 1 μM: (n=8), 12±2*; *p<0.05] as compared to control mice [vehicle: (n=9), 374±53; 0.5 μM: (n=8), 55±14; 1 μM: (n=9), 20±3]. Using fundus, 4-DAMP at 0.5 μM, but not 1 μM, reduced TG (10 μM)-induced contractions in diabetic mice [vehicle: (n=13), 43±13; 0.5 μM: (n=14), 7±8*; 1 μM: (n=14), 13±7; *p<0.05], but not in control mice [vehicle: (n=13), 28±10; 0.5 μM: (n=11), 10±10; 1 μM: (n=11), 24±9]. 4-DAMP (0.5, 1, 10 μM) did not alter TG (10 μM)-induced relaxation of antrum from control or diabetic mice. In diabetic, but not control mice, TG-induced contractions of fundus were reduced by 4-DAMP, suggesting an additional non-cholinergicmechanism for TG-induced contraction in control mice. Both gastric region and type 2 diabetes may alter the effectiveness of prokinetic agents in accelerating gastric emptying. Supported by College of Health Sciences and ORSP at MWU.

Development and in vitro evaluation of colonic drug delivery systems for tegaserod maleate

Interest exists in developing site-specific systems of release of drug in the colon via the oral route. Tegaserod maleate was used as a drug for irritable bowel syndrome, whereas Eudragit L 100 and S100 mixture (1:1, 1:2, and 1:3) were used as pH-sensitive polymers. Various approaches, namely microcapsules, compressed microcapsules, and modified tablets were made for this study. The microcapsules were prepared by the emulsion–solvent evaporation method using drug and mixture of polymers. The prepared microcapsules were evaluated for various physicochemical parameters such as particle size, surface morphology, drug loading capacity, and in vitro dissolution studies by half-dilution method employing various pH environments (pH 1.2–6.8) for 24 hours. The batch prepared using the 1:2 drug polymer ratio was selected as an ideal batch for compression to get the compressed tablet of the microcapsules. The compressed microcapsules were evaluated for physicochemical parameters such as average weight, hardness, friability, thickness, and in vitro dissolution by the halfdilutionmethod. The modified tablets were also prepared using the drug with hydroxylpropylmethylcellulose as the inner material and ethyl cellulose as the outer material employing the double compression technique. The prepared tablets were subjected to various physicochemical parameters, including thickness, weight variation test, drug content, hardness, friability, and in vitro dissolution study using the half-dilution method (pH 1:2–6.8) for 24 hours. Comparisons of microcapsules, compressed microcapsules, and modified tablets containing tegaserod maleate indicated that the drug release profiles from the microcapsules were found to be better than the compressed microcapsules and the modified tablets in the colonic environment.

Development and Evaluation of a pH-Dependent Sustained Release Tablet for Irritable Bowel Syndrome

The overall objective of this study was to develop a pH-dependent sustained release tablet formulation of a model drug, tegaserod maleate (TM), which is a poorly water soluble and acid labile drug in gastric milieu. The formulation's goal was to allow the dosage form to pass through the stomach intact, start disintegrating in the upper small intestine and slowly release the active in a controlled manner. Partition coefficient, contact angle and drug-excipient compatibility were investigated as part of the preformulation studies. A pH-dependent sustained release tablet was prepared using a combination of Eudragit® L100 and Eudragit® S100. The effects of solubilizer, disintegrant, binder, coating polymer concentration, pore former, and plasticizer on the drug release rate were determined. The results demonstrated that approximately 90% of the drug was released in a sustained release manner in the pH 6.8 phosphate buffer within 12 h while no drug was detected when subjected to drug release studies in 0.1 mol/L hydrochloric acid for 2 h. The drug release mechanism involved stress points and/or pore formation in the coated film. The coated tablets were stable at 40°C/75% RH for 3 months. These results highlighted the feasibility of this coated tablet system containing TM, which may contribute to the successful treatment of irritable bowel syndrome.

Estimation of tegaserod maleate by differential pulse polarography

A highly sensitive differential pulse polarographic method has been developed for the estimation of tegaserod maleate after treating it with hydrogen peroxide solution. The oxidation of tegaserod maleate is a reversible process as the oxidized product could be reduced at hanging mercury drop electrode in a quantitative manner using differential pulse polarography mode. The limit of quantification was 0.1ng/ml. The voltametric peak was obtained at -1.05 volts in presence of 0.1M potassium chloride as supporting electrolyte. The technique could be used successfully to analyze tegaserod maleate in its tablet formulation.

Development andin vitroevaluation of colonic drug delivery systems for tegaserod maleate

Development and<i>in vitro</i>evaluation of colonic drug delivery systems for tegaserod maleate

1055 Tegaserod (TEG) Reduces Brain Responses to Rectal Distension in IBS-C Patients: A Functional Magnetic Resonance Imaging (fMRI) Study

1055 Tegaserod (TEG) Reduces Brain Responses to Rectal Distension in IBS-C Patients: A Functional Magnetic Resonance Imaging (fMRI) Study

Crystalline forms and aqueous solubilities of an IBSdrug, tegaserod

Tegaserod is shown to exist in the tautomeric form II in the free base and also in a monohydrate. The Tegaserod nicotinate salt has a 6-fold better aqueous solubility than the marketed Tegaserod maleate (form A, Zelnorm™).

Determination of tegaserod by LC–ESI-MS/MS and its application to a pharmacokinetic study in healthy Chinese volunteers

A simple, rapid and sensitive high performance liquid chromatography–electrospray ionization-tandem mass spectrometry (HPLC–ESI-MS/MS) assay for determination of tegaserod in human plasma using diazepam as internal standard (IS) was established. After adjustment to a basic pH with sodium hydroxide, plasma was extracted by ethyl acetate and separated by high performance liquid chromatography (HPLC) on a reversed-phase C 18 column with a mobile phase of methanol: 5 mM ammonium acetate (75:25, v/v, adjusting the pH to 3.5 with glacial acetic acid). The quantification of target compounds was obtained by using multiple reaction monitoring (MRM) transitions; m/ z 302.5, 173.2 and 285.4, 193.2 were measured in positive mode for tegaserod and internal standard (diazepam), respectively. The lower limit of quantification (LLOQ) was 0.05 ng/ml. The calibration curves were linear over the range 0.05–8.0 ng/ml ( r = 0.9996) for tegaserod. The mean absolute recovery of tegaserod was more than 85.56%. Intra- and inter-day variability values were less than 9.21% and 10.02%, respectively. The samples were stable for 8 h under room temperature (25 °C, three freeze–thaw cycles in 30 days and for 30 days under −70 °C). After administration of a single dose of tegaserod maleate 4 mg, 6 mg and 12 mg, respectively, the area under the plasma concentration versus time curve from time 0 h to 12 h (AUC 0–12) were (2.89 ± 0.88), (5.32 ± 1.21) and (9.38 ± 3.42) ng h/ml, respectively; peak plasma concentration ( C max) were (1.25 ± 0.53), (2.21 ± 0.52) and (4.34 ± 1.66) ng/ml, respectively; apparent volume of distribution ( V d /F) were (6630.5 ± 2057.8), (7615.2 ± 2242.8) and (7163.7 ± 2057.2) l, respectively; clearance rate (CL /F) were (1851.4 ± 496.9), (1596.2 ± 378.5) and (1894.2 ± 459.3) l/h, respectively; time to C max ( T max) were (1.00 ± 0.21), (1.05 ± 0.28) and (1.04 ± 0.16) h, respectively; and elimination half-life ( t 1/2) were (3.11 ± 0.78), (3.93 ± 0.92) and (3.47 ± 0.53) h, respectively; MRT were (3.74 ± 0.85), (4.04 ± 0.56) and (3.28 ± 0.66) h, respectively. The essential pharmacokinetic parameters after oral multiple doses (6 mg, b.i.d) were as follows: C ssmax, (2.72 ± 0.61) ng/ml; T max, (1.10 ± 0.25) h; C ssmin, (0.085 ± 0.01) ng/ml; C av, (0.54 ± 0.12) ng/ml; DF, (4.84 ± 0.86); AUC ss, (6.53 ± 1.5) ng h/ml. This developed and validated assay method had been successfully applied to a pharmacokinetic study after oral administration of tegaserod maleate in healthy Chinese volunteers at a single dose of 4 mg, 6 mg and 12 mg, respectively. The pharmacokinetic parameters can provide some information for clinical medication.