Discovery of DA-1229: a potent, long acting dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes.

A series of ß-amino amide containing substituted piperazine-2-one derivatives was synthesized and evaluated as inhibitors of dipeptidyl pepdidase-4 (DPP-4) for the treatment of type 2 diabetes. As results of intensive SAR study of the series, (R)-4-[(R)-3-amino-4-(2,4,5-trifluorophenyl)-butanoyl]-3-(t-butoxymethyl)-piperazin-2-one (DA-1229) displayed potent DPP-4 inhibition pattern in several animal models, was selected for clinical development.

Udenafil enhances the recovery of erectile function and ameliorates the pathophysiological consequences of cavernous nerve resection.

INTRODUCTION: Radical prostatectomy is the treatment of choice for prostate cancer patients. Despite the introduction of nerve-sparing surgical techniques, its success is not entirely guaranteed and the majority of patients report compromised erectile function following surgical procedures. AIM: This study was performed to investigate the effect of repeated dosing of udenafil, a novel phosphodiesterase type 5 inhibitor, on penile hypoxia and fibrosis induced by bilateral cavernous nerve resection (BCNR) in rats. METHODS: Thirty male Sprague-Dawley rats (300-320 g) were used in this study. The animals were divided into three groups; group I consisted of sham-operated animals (N = 10), animals in group II underwent BCNR alone (N = 10), and animals in group III were orally treated with 10 mg/kg udenafil b.i.d. for 8 weeks following BCNR (N = 10). MAIN OUTCOME MEASURES: The expression of transforming growth factor-beta1, hypoxia-inducible factor-1 alpha, endothelial nitric oxide synthase, neuronal nitric oxide synthase, and endothelin B receptor in penile tissue was examined at gene level. Additionally, erectile function, measured by intracavernous pressure (ICP), and pathological changes in the corpus cavernosum were examined. RESULTS: While fibrosis, apoptosis, and the expression of TGF-beta1, HIF-1 alpha, and ET(B) were significantly increased, and the expression of eNOS and nNOS were significantly decreased in group II, compared with the sham-operated animals, repeated dosing of udenafil significantly ameliorated these changes. Erectile function was profoundly impaired in animals that underwent BCNR alone, and udenafil treatment significantly attenuated this impairment as measured by ICP. CONCLUSIONS: These results demonstrate that long-term administration of udenafil ameliorates penile hypoxia and fibrosis induced by cavernous nerve resection. This study also suggests the potential beneficial role of repeated dosing of udenafil in the recovery of erectile function in patients with neuronal erectile dysfunction.

The therapeutic effect of DA-6034 on ocular inflammation via suppression of MMP-9 and inflammatory cytokines and activation of the MAPK signaling pathway in an experimental dry eye model.

PURPOSE: To investigate the effect of DA-6034, 7-carboxymethyloxy-3',4',5-trimethoxy flavone, in experimentally-induced inflammatory dry eye in rabbit. In addition, to elucidate the mechanism of DA-6034, we evaluated the mitogen-activated protein kinase (MAPK) signaling pathway and transcriptional factor-kappa B (NF-kB) in corneal epithelial cells. METHODS: Rabbit lacrimal glands were injected with the T-cell mitogen concanavalin A (Con A). DA-6034 was then administered topically four times a day for six days starting 24 hr after Con A injection. Tear volume, tear function, MMP-9 and inflammatory cytokine levels in the lacrimal glands, and histological evaluation were subsequently assessed. In in vitro study, phosphorylated MAPKs (c-Jun NH2-terminal kinase (JNK) and p38 MAPK) and NF-kB were detected by enzyme-linked immunosorbent assay (ELISA) using human corneal epithelial cells. RESULTS: A single injection of Con A into the lacrimal glands induced a pronounced inflammatory response, caused elevated levels of MMP-9 and cytokines IL-8 and TGF-beta(1), and induced a decrease in tear volume and shortening of tear breakup time (TBUT). In this inflammation model of dry eye, DA-6034 clearly showed therapeutic efficacy by restoring tear function and inhibiting inflammatory responses after topical ocular application. Furthermore, DA-6034 attenuated the phosphorylation of JNK and p38 MAPK and inhibited NF-kB activation in a concentration-dependent manner in corneal epithelial cells. CONCLUSIONS: These results suggest that DA-6034 has the therapeutic effect in rabbit lacrimal gland inflammation model of dry eye and might be a potential treatment option for acute dry eye syndrome.

Effects of DA-6034, a flavonoid derivative, on mucin-like glycoprotein and ocular surface integrity in a rabbit model.

This study was designed to assess whether DA-6034 (7-carboxymethyloxy-3',4',5-trimethoxy flavone monohydrate), a new synthetic derivative of eupatilin, increases secretion of mucin-like glycoprotein and some mucins species in conjunctiva and cornea, and contributes to the preservation of ocular surface integrity. Human conjunctival and corneal epithelial cells were incubated with DA-6034 (1-250 microM). To investigate mucin secreting activity more directly, isolated rat conjunctival goblet cells were also used. Corneal protection was investigated using a desiccation-induced rabbit model of dry eye syndrome. It was found that DA-6034 increased mucin-like glycoprotein levels of both conjunctival and corneal epithelial cells at concentrations above 100 microM. Using human conjunctival epithelial cells, it was demonstrated that treatment with DA-6034 (200 microM) significantly increased production of some mucins species including MUC1, MUC2, MUC4, MUC5AC, MUC5B, and MUC16. DA-6034 also significantly increased MUC5AC production from conjunctival goblet cells isolated from rats. In the rabbit desiccation model, an ophthalmic suspension containing 3% DA-6034 significantly reduced corneal damage induced by desiccation. These results suggest that DA-6034 is a good candidate for treatment of dry eye through maintaining ocular surface integrity, which might be related to mucin secretion.

Effects of DA-6034 on aqueous tear fluid secretion and conjunctival goblet cell proliferation.

PURPOSE: This study was conducted to evaluate the effect of DA-6034, a potent secretagogue, on aqueous tear fluid secretion and its quality in normal rabbit. We also evaluated, in animal models of experimentally induced dry eye disease, its effectiveness over time to stimulate aqueous tear production by ocular ferning test and goblet cell proliferation. METHODS: Aqueous tear production, total protein levels, and glycoprotein levels in normal rabbits were evaluated after topical application of DA-6034 (0.3, 1, and 3%). Moreover, time course aqueous tear volume measurement and ocular ferning test in tear fluid were performed in dry eyes of rabbits that had been given 1% atropine sulfate, topically. Altogether, tear fluid production and conjunctival goblet cell numbers were measured in dry eyes of mice that had been given topical scopolamine. RESULTS: Topical application of DA-6034 (0.3, 1, and 3%) significantly increased (P < 0.05) aqueous tear production in a concentration-dependent manner in normal rabbits. There was no change in total protein levels while glycoprotein levels were significantly increased (P < 0.05) at 3% DA-6034. The increase in aqueous tear fluid was significant (P < 0.05) and lasted for 2 h post-instillation in dry eyes of rabbits that had been given 1% atropine sulfate; 10-day repeated instillation of the drug in this model resulted in large and homogeneous fern-like tear patterns. In a mouse model, DA-6034 given as a 3% eyedrop solution significantly increased (P < 0.05) tear fluid production and conjunctival goblet cell number. CONCLUSIONS: These results suggest that DA-6034 accelerates not only tear secretion but also mucin production and may be a potential therapeutic agent for the treatment of dry eye disease.

Beneficial effects of the combination of amlodipine and losartan for lowering blood pressure in spontaneously hypertensive rats.

A combination of antihypertensive agents can better control blood pressure and reduce the number and severity of side effects than a monotherapy. Since both CCBs (calcium channel blockers) and ARBs (angiotensin II receptor type-1 blockers) are current and effective antihypertensive drugs, this study assessed the synergistic antihypertensive effects as well as the optimal combination ratio of these two drugs. Amlodipine (3 mg/kg) or losartan (30 mg/kg) alone or a combination of each drug at a ratio 1:10 and 1:20 was administered orally to spontaneously hypertensive rats (SHR). A four-week treatment of either 3 mg/kg amlodipine or 30 mg/kg losartan alone decreased the systolic blood pressure (SBP). However, their combination significantly lowered the SBP from the 3(rd) week, and there was a positive correlation between this reduction in blood pressure and the improvement in arterial endothelium-dependent relaxation. In addition, the combination therapy (1:20) decreased both the cardiac mass and left ventricular weight to a greater extent than with either amlodipine or losartan alone. The collagen content in the cardiac tissue was also significantly lower after the 4-week combination therapy (1:10). These results suggest that the combined use of amlodipine and losartan might be more effective in treating hypertension than a monotherapy.

Effect of udenafil on portal venous pressure and hepatic fibrosis in rats. A novel therapeutic option for portal hypertension.

The purpose of this study was to investigate the therapeutic efficacy of udenafil (CAS 268203-93-6), a phosphodiesterase type 5 (PDE5) inhibitor, on bile duct ligation (BDL)-induced portal hypertension. Udenafil was given orally to rats at dose levels of 1, 5 or 25 mg/kg/day for 3 weeks in order to examine the chronic effect on portal venous pressure (PVP). Udenafil was also given orally to investigate the sequential change of PVP in BDL animals. The effect of udenafil on hepatic stellate cell activation and fibrotic change-related protein mRNA expression were examined. In a pharmacokinetic study, the pharmacokinetic parameters in sham-operated rats and BDL rats were compared. Three-week udenafil treatment decreased PVP by approximately 30% compared to the vehicle group. In a single oral administration study, the PVP of the udenafil treated group was lower than that of the control group throughout the experimental period. Compared to control, udenafil suppressed the expression of procollagen type I and alpha-smooth muscle actin mRNA. In the pharmacokinetic study, the AUC of udenafil in BDL rats was approximately 5 times higher than that in sham-operated rats. The results of this study suggest that udenafil has beneficial effects on portal hypertension and the effect may well be attributed to its anti-fibrogenic activity.

Gastroretentive drug delivery system of DA-6034, a new flavonoid derivative, for the treatment of gastritis.

A gastroretentive drug delivery system of DA-6034, a new synthetic flavonoid derivative, for the treatment of gastritis was developed by using effervescent floating matrix system (EFMS). The therapeutic limitations of DA-6034 caused by its low solubility in acidic conditions were overcome by using the EFMS, which was designed to cause tablets to float in gastric fluid and release the drug continuously. The release of DA-6034 from tablets in acidic media was significantly improved by using EFMS, which is attributed to the effect of the solubilizers and the alkalizing agent such as sodium bicarbonate used as gas generating agent. DA-6034 EFMS tablets showed enhanced gastroprotective effects in gastric ulcer-induced beagle dogs, indicating the therapeutic potential of EFMS tablets for the treatment of gastritis.

Transport of a new erectogenic udenafil in Caco-2 cells.

P-glycoprotein, an ATP-dependent efflux pump, is a membrane transporter that influences the absorption and excretion of drugs. There is a striking overlap between the substrates for CYP3A4 and P-glycoprotein. This study was designed to assess whether udenafil, a substrate of CYP3A4, is also a P-glycoprotein substrate. Udenafil stimulated P-glycoprotein ATPase activity, a putative measure of P-glycoprotein affinity, although with lower affinity than a proven substrate, verapamil. Bidirectional transport studies of udenafil using Caco-2 cell monolayers showed that its efflux (15.9-22.8 x 10(-6) cm/s) was significantly higher than its influx (3.7-9.1 x 10(-6) cm/s). P-glycoprotein inhibitors such as cyclosporine, tariquidar and verapamil significantly increased the influx of udenafil and decreased the efflux of udenafil. These results indicate that udenafil is a substrate for P-glycoprotein. The low bioavailability, variable absorption and drug-drug interactions of udenafil may be related to the variability of CYP3A4 and P-glycoprotein expression and to possible CYP3A4 and P-glycoprotein interactions.

Effects of phosphodiesterase type 5 inhibitor on the contractility of prostate tissues and urethral pressure responses in a rat model of benign prostate hyperplasia.

AIM: This study was performed to investigate the effect of DA-8159, a selective phosphodiesterase 5 (PDE5) inhibitor, on benign prostatic hyperplasia (BPH) both in vitro and in vivo. METHODS: We assessed the influence of DA-8159 on the contractility of rat prostate tissues in an organ-bath experiment. In addition, in order to investigate whether chronic administration of DA-8159 prevents the increase of electrostimulation-induced intraurethral pressure (IUP) responses associated with BPH, BPH was induced by steroid hormones (testosterone plus 17beta-estradiol) and DA-8159 (5, 20 mg/kg) was concomitantly administered once a day for 8 weeks. After that the electrostimulation-induced IUP responses were measured. Finally, we investigated the acute treatment effect of DA-8159 on IUP responses in an established BPH model after a single intravenous injection of DA-8159 (0.3, 1 mg/kg). RESULTS: DA-8159 concentration-dependently reduced the contraction of the isolated prostate strips with an IC50 value of 70 microM. In chronic treatment study, while the BPH control rats showed a significantly increased IUP both at the baseline and by electrostimulation, the chronic DA-8159 treatment significantly attenuated the increase in IUP responses in a dose- and frequency-dependent manner. In the acute treatment study, a single intravenous injection of DA-8159 also prevented the increase in urethral pressure in a dose-dependent manner. CONCLUSIONS: These results suggest that DA-8159 may be beneficial on lowering the urethral pressure associated with BPH via dilatation of the prostate, but a further evaluation of the efficacy on humans needs to be performed.

Pharmacokinetics of DA-7218, a new oxazolidinone, and its active metabolite, DA-7157, after intravenous and oral administration of DA-7218 and DA-7157 to rats.

DA-7218 (a prodrug of DA-7157), a new oxazolidinone, was hydrolysed via phosphatase to form its active metabolite, DA-7157, in rats. The pharmacokinetic parameters of DA-7218 and DA-7157 were evaluated after intravenous (5, 10 and 20 mg kg(-1)) and oral (20, 50 and 100 mg kg(-1)) administration of DA-7218 to rats. DA-7218 and DA-7157 exhibited dose-proportional pharmacokinetics after both intravenous and oral administration of DA-7218 to rats. The stability of DA-7218 and DA-7157, blood partition of DA-7157, and the plasma protein binding of DA-7157 were also evaluated. DA-7218 was unstable in rat blood, plasma, bile and liver homogenates, but DA-7157 was stable, suggesting that DA-7218 is hydrolysed via phosphatase. DA-7157 rapidly reached equilibrium between plasma and blood cells, and the mean equilibrium plasma-to-blood cells ratio was 3.18, indicating that binding of DA-7157 to blood cells was not considerable. The protein binding of DA-7157 in fresh rat plasma was 93.4%.

Gastroprotective effects of DA-6034, a new flavonoid derivative, in various gastric mucosal damage models.

This study evaluated the gastroprotective activity of DA-6034 against various ulcerogens including ethanol, aspirin, indomethacin, stress, and acetic acid. The basic mechanisms of DA-6034 as a defensive factor such as mucus secretion and endogenous prostaglandin E(2) synthesis were determined. Rats with gastric lesions induced by ethanol-HCl, aspirin, indomethacin, and stress that had been pretreated with DA-6034 orally showed a statistically significant decrease or decreasing tendency of the gastric lesion. In acetic acid-induced gastric lesions, repeated oral administration of DA-6034 exhibited a U-shape activity in ulcer healing, with the maximum and minimum inhibition being observed at 30 and 10 mg/kg/day, respectively. DA-6034 also increased the mucus content in the gel layer as well as endogenous prostaglandin E(2) synthesis. These results suggest that DA-6034 prevents gastric mucosal injury, and these gastroprotective activities appear to be due to the increase in the gastric defensive systems.

Inhibitory effects of 7-carboxymethyloxy-3',4',5-trimethoxyflavone (DA-6034) on Helicobacter pylori-induced NF-kappa B activation and iNOS expression in AGS cells.

The Helicobacter pylori were identified by Marshall and Warren in 1984. H. pylori survive in the forbidding harsh acid environment of the stomach and duodenum by hiding in the mucus layer and neutralizing gastric acid in its local surrounding environment. Multiple lines of evidence suggest that H. pylori infection is one of the primary causes of gastritis and peptic ulcer, which are provoked by oxidative stress and inflammation. More than 50% of the world's population is infected by this bacterium. The H. pylori-induced inflammation has been implicated in the pathogenesis and progression of gastric cancer. DA-6034 (7-carboxymethyloxy-3',4',5-trimethoxy flavone) is a synthetic flavonoid known to possess anti-inflammatory activity. It has been reported that oral administration of DA-6034 suppresses the inflammatory bowel disease (IBD) in animal models. In this article, we attempted to examine the effect of DA-6034 on H. pylori-induced inflammation in human gastric cancer (AGS) cells by targeting NF-kappaB and extracellular signal-regulated kinase (ERK), a representative MAPK.

Microarray analysis of gene expression profile in the corpus cavernosum of hypercholesterolemic rats after chronic treatment with PDE5 inhibitor.

Gene expression changes in the corpus cavernosum of hypercholesterolemic rats were not fully assessed, which were not previously known to be associated with hypercholesterolemia-related erectile dysfunction (ED). To provide molecular insight into pathophysiology of hypercholesterolemia-related ED and to investigate the effects of Udenafil, a phosphodiesterase type 5 (PDE5) inhibitor, on gene expression, we performed microarray gene expression analysis via gene discovery methods using GenoCheck platinum cDNA chip (Ansan, S. Korea). Sixteen male Sprague-Dawley rats were fed 2% cholesterol diet for 5 months. Half of them were orally treated with Udenafil (20 mg/kg/day) simultaneously. Eight age-matched rats fed normal diet were served as normal control. RNA was extracted from corpus cavernosum and microarray analysis was performed. Decreased erectile responses and hypercholesterolemia were observed in hypercholesterolemic control group. In microarray analysis, 122 candidate genes were noted to be altered based on the magnitude of expression changes, which includes 44 down-regulated and 78 up-regulated genes compared with the age-matched normal controls. These changes were, however, significantly attenuated by treatment with Udenafil. Out of the 78 up-regulated genes, 8 genes were significantly decreased by the chronic treatment with Udenafil. The altered genes were cytochrome oxidase biogenesis protein OXA1, skeletal muscle myosin heavy chain, lipophilin, fast skeletal muscle isoforms beta/alpha, myosin light chain 3, cytochrome c oxidase, adipocyte fatty acid binding protein and one EST gene. In contrast, among the 44 down-regulated genes, Kruppel-like factor 5 and cyclin D1 genes were increased after the Udenafil treatment. These results provide the molecular basis for understanding the pathogenesis of hypercholesterolemia-related ED and offer clues on determining the underlying action mechanism of a PDE5 inhibitor.

Effects of water deprivation on the pharmacokinetics of DA-8159, a new erectogenic, in rats.

PURPOSE: To test the effect of 72 h water deprivation on the non-renal clearance (CL) of DA-8159 in a rat model of dehydration. DA-8159 is mainly metabolized via CYP3A1/2 and the expression and mRNA level of CYP3A1/2 are not affected by dehydration. METHODS: DA-8159 (30 mg/kg) was administered intravenously or orally to male control Sprague Dawley rats and rat model of dehydration. RESULTS: As expected, after intravenous administration, the CL(NR) values of DA-8159 were comparable between two groups of rats. This could be supported by comparable intrinsic CL of DA-8159 using hepatic microsomes for both groups of rats. However, the CL was significantly slower in rat model of dehydration due, at least in part, to significantly slower renal CL in rat model of dehydration. The slower CL(R) in rat model of dehydration could be due to urine flow ratedependent renal CL of DA-8159; the less urine output, the less the urinary excretion of unchanged DA-8159. After oral administration, the AUC values of DA-8159 were not significantly different between two groups of rats, although the AUC of DA-8159 in rat model of dehydration was significantly greater than controls after intravenous administration. This could be possibly due to changes in the intestinal first-pass effects in rat model of dehydration. CONCLUSIONS: After intravenous administration of DA-8159, the non-renal CL values were comparable between two groups of rats due to the lack of effect of dehydration on CYP3A1/2.

Inhibitory effect of DA-9201, an extract of Oryza sativa L., on airway inflammation and bronchial hyperresponsiveness in mouse asthma model.

Asthma is one of the major public health problems worldwide and the morbidity and mortality of asthma has increased in the past two decades. Accumulating data suggest that unnecessary immune responses and inflammation should be suppressed to treat asthma. The purpose of this study is to investigate the anti-asthmatic effects of DA-9201, an ethanolic extract of black rice (Oryza sativa L. var japonica), on an ovalbumin (OVA)-induced mouse model of asthma. Balb/c mice immunized with OVA were administered with DA-9201 (30, 100 or 300 mg/kg, p.o.) or dexamethasone (3 mg/kg, p.o.) and challenged with 1% aerosolized OVA for 30 min. The effects on airway inflammation, airway hyperresponsiveness (AHR), antibody profiles and cytokines were evaluated. DA-9201 treatment significantly reduced the number of eosinophils in bronchoalveolar lavage fluid (BALF) and ameliorated the AHR. Lung histological features also showed that DA-9201 reduced airway inflammation. Furthermore, DA-9201 treatment decreased IFN-gamma as well as IL-4, IL-5 and IL-13 levels in the supernatant of cultured splenocytes, and suppressed the level of OVA-specific IgG, IgG2a, IgG1 and total IgE in plasma. DA-9201 showed anti-asthmatic effects by suppressing unnecessary immune responses, airway inflammation, eosinophilia, AHR and IgE level. These results suggest DA-9201 might be beneficial for the treatment of asthma.

Erectile potentials of a new phosphodiesterase type 5 inhibitor, DA-8159, in diet-induced obese rats.

AIM: To examine the changes in the erectile function in diet-induced obese rats and investigate the oral efficacy of DA-8159, a new phosphodiesterase type 5 (PDE5) inhibitor, on penile erection in obese rats. METHODS: The rats were fed a high-energy diet for 12 weeks and divided into three groups: an obesity-resistant (OR) control group, an obesity-prone (OP) control group, and an OP-DA-8159 treatment (DA-8159) group. The electrostimulation-induced erectile responses were measured in all groups. The body weight, plasma cholesterol, triglyceride and glucose levels were also measured. RESULTS: In the OP control group, the maximum intracavernous pressure (ICP) and ICP/blood pressure (ICP/BP) ratio after electric stimulation were significantly lower than those in OR control group. The corresponding area under the curve (AUC) of the ICP/BP ratio, the detumescence time and the baseline cavernous pressure were also lower than those in the OR control group, but this difference was not significant. The body weight gain, plasma cholesterol and triglyceride level in the OP group were significantly higher than those in the OR group. After administering the DA-8159, a significant increase in the maximum ICP and the ICP/BP ratio were observed. The corresponding AUCs in the DA-8159 group were also higher than those in the two control groups. Furthermore, the detumescence time was significantly prolonged after treatment with DA-8159. CONCLUSION: These results demonstrate that diet-induced obesity affects the erectile function in rats and these erectile dysfunction (ED) can be improved by the treatment with DA-8159, indicating DA-8159 might be a treatment option for ED associated with obesity.

Effect of Oryza sativa extract on the progression of airway inflammation and remodeling in an experimental animal model of asthma.

Airway inflammation and remodeling in chronic asthma are characterized by airway eosinophilia, hyperplasia of smooth muscle and goblet cells, and subepithelial fibrosis. The present study was undertaken to evaluate the effects of DA-9201, an ethanolic extract of black rice (Oryza sativa L.), on airway inflammation and remodeling in a murine model of chronic asthma. BALB/c mice sensitized to ovalbumin (OVA) were chronically challenged with aerosolized OVA for 6 weeks. DA-9201 (30, 100, or 300 mg/kg) or dexamethasone (3 mg/kg) was orally administered during the last 4 and 2 weeks, respectively. Airway inflammation, lung pathology by histomorphometry and immunohistochemistry, IgE level and Th2 cytokines were evaluated. The OVA-treated mice showed extensive eosinophilia, chronic inflammatory responses and characteristics of airway remodeling including subepithelial fibrosis, smooth muscle hypertrophy, and goblet cell hyperplasia. As compared to the OVA-treated control group, treatment with DA-9201 resulted in significant reductions in the accumulation of eosinophils in peribronchial areas, chronic pulmonary inflammation and progression of airway remodeling. Furthermore, DA-9201 significantly reduced total serum and BALF IgE levels and Th2 cytokines. These results indicate that DA-9201 may play an important role in attenuating the progressing of airway inflammation and remodeling and suggest the potential benefits of DA-9201 in prevention or treatment of asthma.

Pharmacokinetics of 7-carboxymethyloxy-3',4',5-trimethoxy flavone (DA-6034), a derivative of flavonoid, in mouse and rat models of chemically-induced inflammatory bowel disease.

The pharmacokinetics (including distribution in the gastrointestinal tract) of 7-carboxymethyloxy-3',4',5-trimethoxy flavone (DA-6034) has been investigated in several mouse and rat models of chemically-induced inflammatory bowel disease (IBD). In the female ICR mouse model, IBD was induced by dextran sulfate and the mice administered 30 mg kg(-1) DA-6034 intravenously or orally. In the male SJL mouse model of IBD induced by oxazolone, 30 mg kg(-1) DA-6034 was administered orally. In the male Sprague-Dawley rat model of IBD induced by trinitrobenzene sulfonic acid (TNBS), 10 mg kg(-1) DA-6034 was administered intravenously and orally. After intravenous administration, the total area under the plasma concentration-time curve from time zero to the last measured time, t, in plasma (AUC(0-t)) values were comparable between control and dextran sulfate-induced IBD mice, and between control and TNBS-induced rats. This suggested that the disposition of DA-6034 was not affected considerably by dextran sulfate in mice and TNBS in rats. However, after oral administration in mice and rats with IBD, the AUC(0-t) values were greater compared with the respective controls. This could have been due to an increase (slow) in the gastrointestinal transit time (in IBD mice and rats, the percentages of the oral dose recovered from the rinsing fluid of the small intestine and large intestine as unchanged drug were greater and smaller, respectively), and an increase in intestinal permeability.

Pharmacokinetics of DA-6034, an agent for inflammatory bowel disease, in rats and dogs: Contribution of intestinal first-pass effect to low bioavailability in rats.

The pharmacokinetics of DA-6034 in rats and dogs and first-pass effect in rats were examined. After intravenous administration, the dose-normalized AUC(0-infinity) values at 25 and 50mg/kg were significantly smaller than that at 10mg/kg. This could be due to significantly slower Cl(r) values than that at 10mg/kg, possibly due to saturated renal secretion at doses of 25 and 50mg/kg. After oral administration, the dose-normalized AUC(0-12h) values at 50 and 100mg/kg were significantly smaller than that at 25mg/kg, possibly due to poor water solubility of the drug. The low F-value (approximately 0.136%) of DA-6034 at a dose of 50mg/kg in rats could be due to considerable intestinal first-pass effect (approximately 69% of oral dose) and unabsorbed fraction from the gastrointestinal tract (approximately 30.5%). The effect of cola beverage, cimetidine, or omeprazole on the AUC(0-24h) of DA-6034 was almost negligible in rats. Pharmacokinetic parameters of DA-6034 after intravenous and oral administration at various doses were dose-independent in dogs. DA-6034 was not accumulated in rats and dogs after consecutive 7 and 28 days oral administration, respectively. The stability, blood partition, and protein binding of DA-6034 were also discussed.