Oral Administration In Rats Research Articles

Structure-Activity Relationships of New N-Acylanthranilic Acid Derivatives as Plasminogen Activator Inhibitor-1 Inhibitors

Novel anthranilic acid derivatives having substituted N-acyl side chains were designed and synthesized for evaluation as plasminogen activator inhibitor-1 (PAI-1) inhibitors. Compounds with a 4-diphenylmethyl-1-piperazinyl moiety on the acyl side chains in general exhibited potent in vitro PAI-1 inhibitory activity and good pharmacokinetic profiles after oral administration in rats. Compound 16f (TM5275) was identified as a promising candidate for further pharmacological evaluation.

Protective effect of Funalia trogii crude extract on deltamethrin-induced oxidative stress in rats

In this study the protective effects of cold buffer extract of Funalia trogii ATCC 200800 (FtE) and vitamin E (VitE) on oxidative stress induced with deltamethrin using oral administration in rats were investigated. Deltamethrin treatment caused an increase in liver enzyme activities of aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP) ( p < 0.05); however, it caused a decrease in activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GRd) when compared to control group ( p < 0.05). Activities of AST, ALT, ALP enzymes and level of thiobarbituric acid reactive substances (TBARS) decreased significantly after VitE administration ( p < 0.05). Both enzyme activities and TBARS levels were found similar in VitE and FtE treated rats shortly after pesticide administration ( p < 0.05). In conclusion, it appears that FtE prepared in cold buffer has capability to prevent the liver damage like VitE against the toxic effect of deltamethrin.

Validation of the FOB method following a single oral administration in rat

Validation of the FOB method following a single oral administration in rat

Pharmacokinetics of lipoyl vildagliptin, a novel dipeptidyl peptidase IV inhibitor after oral administration in rats

The pharmacokinetics of lipoyl vildagliptin, a novel dipeptidyl peptidase IV (DPP IV) inhibitor, was studied in rats after oral administration for developing it as an antidiabetic agent.A liquid chromatography-tandem mass spectroscopy (LC-MS/MS) method was developed to determine lipoyl vildagliptin in rat plasma. After an overnight fasting, rats were orally given lipoyl vildagliptin. Following a single oral dose of 25, 50, and 100 mg·kg−1, Tmax values were from 1.25 to 1.84 h, CL/F values were around 100 l h−1 kg−1. In the dose range, Cmax values (63.9–296 μg·l−1) and AUC0–∞values (260–1214 μg·h·l−1) were proportional to the doses.In conclusion, this LC-MS/MS method for the determination of lipoyl vildagliptin in rat plasma was selective and sensitive. In rats, lipoyl vildagliptin displayed linear pharmacokinetics after a single oral dose in the range of 25–100 mg·kg−1. Lipoyl vildagliptin might have very high CL/F values and Vd/F values, which indicated that the bioavailability of this drug might be low or lipoyl vildagliptin might distribute extensively or accumulate in tissues in view of its high liposolubility.

Preparation and evaluation of a self-emulsifying drug delivery system of etoposide–phospholipid complex

Aim: The aim of this study was to develop a new phospholipid complex self-emulsifying drug delivery system (PC-SEDDS) to enhance bioavailability of oral etoposide, a drug with poor water solubility. Methods: Etoposide–phospholipid complex (EPC) was prepared by reacting etoposide and phospholipid in tetrahydrofuran and confirmed as a phospholipid compound by differential scanning calorimetry (DSC). Solubility of EPC and etoposide was determined in various vehicles. Pseudoternary phase diagrams were constructed to identify the efficient self-emulsification region of EPC-SEDDS, and the effects of oil concentration, drug loading, and aqueous media on droplet size were investigated. Results: The optimal formulation of EPC-SEDDS was EPC:octyl and decyl monoglyceride (ODO):Cremopher EL:PEG-400 (1:20:48:32) (w/w/w/w). Compared with etoposide–phospholipid complex suspension (EPCS) and etoposide suspension (ES), cumulative release of etoposide from EPC-SEDDS increased by 1.31 and 2.65 fold at 24 hours, respectively. Compared with ES, relative bioavailability of EPC-SEDDS, E-SEDDS, and EPCS after oral administration in rats was enhanced by 60.21-, 44.9-, and 8.44- fold, respectively. Conclusions: The synergistic effect between PC and SEDDS contributed to the enhanced bioavailability of etoposide. It was concluded that PC-SEDDS proved to be a potential system for delivering orally administered hydrophobic compounds including etoposide.

A liquid chromatography–tandem mass spectrometry method for the quantification of PAC-1 in rat plasma

A sensitive and specific liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) method was developed and validated for the determination of PAC-1 in rat plasma. After extraction with ethyl acetate, the chromatographic separation was carried out on an ACQUITY UPLC™ BEH C 18 column, with acetonitrile and water (39:61 (v/v) both containing 0.1% formic acid) as mobile phase at a flow rate of 0.20 mL/min. The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring (MRM) mode via electrospray ionization (ESI) source. The calibration curve was linear over the range of 10–1500 ng/mL ( r > 0.99). The LOQ was evaluated to be 0.3 ng/mL. The method described herein is sensitive, selective and faster than other existing method, and was successfully applied to the pharmacokinetic study and gender difference investigation of PAC-1 after oral administration in rats.

Intestinal Absorption of HMG-CoA Reductase Inhibitor Pravastatin Mediated by Organic Anion Transporting Polypeptide

The purpose of this study is to clarify the impact of organic anion transporting polypeptide (Oatp) on intestinal absorption of the HMG-CoA reductase inhibitor, pravastatin. OATP/Oatp-mediated pravastatin uptake was evaluated with Xenopus oocytes systems. Intestinal permeability was measured by an in situ closed loop method in rats. In vivo pravastatin absorption was kinetically assessed by measuring plasma concentration after oral administration in rats. Uptake of pravastatin by Oatp1a5, Oatp2b1, OATP1A2, and OATP2B1 cRNA-injected Xenopus oocytes was significantly increased compared with that by water-injected oocytes. Naringin, a potent inhibitor of Oatps and Mdr1, decreased the Oatp1a5-mediated uptake of pravastatin with IC (50) value of 30.4μM. Rat intestinal permeability of pravastatin was significantly reduced in the presence of 1,000μM naringin. Similar results were obtained in in vivo absorption studies in rats. Furthermore, no significant change in the permeability was observed in the presence of elacridar, a potent inhibitor of both Mdr1 and Bcrp, though the permeability was significantly decreased in the presence of both elacridar and naringin, suggesting that Mdr1 and Bcrp are not involved in intestinal absorption of pravastatin. Oatp, but not by Mdr1 or Bcrp, contributes to the intestinal absorption of pravastatin in rats.

Otsenka obshchetoksicheskikh svoystv preparata geksasens v eksperimente

The systemic toxic and local irritant effects of the new drug Hexasens used for the fluorescence diagnosis of malignancies were studied on small laboratory animals: mice, rats, and rabbits. The acute and chronic toxicities of the agent were investigated when orally used and its local irritant effect was examined when intravesicularly injected. The conducted studies indicated that Hexasens was a lowly toxic pharmacological agent. Its oral administration in rats at a 5% concentration or less produced no local irritant effect on the esophagus (esophagospasm). Intravesicular injection of Hexasens in rabbits at a 0.01% concentration (containing 1.0 mg of the agent in 10 ml of an injectable solution) or less exerted no local irritant effect on the urinary bladder mucosa.

Synthesis and pharmacological evaluation of 1,1,3-substituted urea derivatives as potent TNF-α production inhibitors

A three substituted urea derivative, SA13353 (compound 1a), exhibited potent inhibitory activity against lipopolysaccharide (LPS)-induced TNF-α production. We focused on the 1,1-substituted moiety (R1 and R2) of SA13353 and investigated substituent effects of this moiety on LPS-induced TNF-α production by oral administration in rats. The synthesis of the urea derivatives was performed rapidly in a one-pot manner using a manual synthesizer. Several compounds containing hydrophobic substituents at this moiety showed more potent inhibitory activities than SA13353.

Gastroresistant microparticles containing sodium alendronate prevent the bone loss in ovariectomized rats

Sodium alendronate, an antiresorptive drug, primarily used in the treatment of osteoporosis was encapsulated in blended microparticles composed of Eudragit ® S100 and Methocel ® K15M. The micropowder obtained by spray-drying technique was characterized in terms of its morphology, particle size, encapsulation efficiency and in vitro drug release. In vivo studies were carried out in order to evaluate the pharmacodynamic effect and the ulcerogenic activity of sodium alendronate-loaded microparticles after oral administration in rats. Drug encapsulation efficiency was close to 80% and particle mean diameter of 13.8 μm. SEM analysis showed spherical collapsed shape particles with smooth surface. At pH 1.2, in vitro experiments showed that <10% of the drug was released from the microparticles. At pH 6.8, the microparticles were able to prolong the sodium alendronate release for 12 h. In vivo experiments carried out in ovariectomized rats showed bone mineral density significantly higher for the sodium alendronate-loaded microparticles than for the negative control groups. Furthermore, the microencapsulation of the drug showed a significant reduction in the ulcerative lesion index. In conclusion, the blended microparticles are excellent oral carriers for sodium alendronate since they were able to maintain the drug antiresorptive effect and to reduce the gastrointestinal drug toxicity.

Gliclazide Microcrystals Prepared by Two Methods of In Situ Micronization: Pharmacokinetic Studies in Diabetic and Normal Rats

The low water-solubility of gliclazide (GL) leads to a low dissolution rate and variable bioavailability. The aim of this study was to investigate the effect of micronization on the absorption and pharmacokinetics of GL after oral administration in rats. GL microcrystals were prepared using solvent-change and pH-shift methods. Scanning electron microscopy showed considerable changes in the shape and size of crystals using both methods. In the optimized formulation of each method, the particle size of treated GL was reduced about 30 (from 290 to 9.9 microm) and 61 times (to 4.76 microm) by solvent-change and pH-shift methods, respectively. Recrystallized samples showed faster dissolution rate than untreated GL particles. Glucose-lowering effect, C(max), and area under the drug concentration-time profile (area under the curve (AUC)) were compared in diabetic and normal rats. AUC and C(max) were increased by microcrystals in both groups of animals. Administration of 40 mg/kg of GL in the form of untreated drug and microcrystals obtained by solvent-change and pH-shift methods caused 12.49% and 21.04% enhancement in glucose-lowering effect of GL in diabetic rats, respectively.

Enhanced Bioavailability of L-Carnitine After Painless Intradermal Delivery vs. Oral Administration in Rats

In vitro and in vivo permeation studies were conducted to evaluate the characteristic of percutaneous administration of high hydrophilic drug L-carnitine (LC) by Functional MicroArray (FMA) painless intradermal delivery system. In vitro study was designed to assess the effects of various skins, donor concentration and hydrogels from different carbomer derivatives on the release of LC in a Franz-type diffusion cell. The LC gel patches with carbomer 980 P were prepared and successfully applied to pharmacokinetic study of SD rats with and without FMA. Intravenous injection and oral administration were performed to support pharmacokinetic calculations and comparison of bioavailability. Enhanced delivery of LC using FMA was achieved in skin of different species in vitro studies. The 750mg LC gel patches were applied to rats over 6h, and approximately 27% of loaded dose was transported into rat. A 2.8-fold enhancement of absolute bioavailability for LC with FMA intradermal delivery system was observed compared with oral LC administration in vivo study. Both in vitro and in vivo studies demonstrated that the FMA intradermal delivery system can enhance the delivery and bioavailability of LC.

Development of a polymeric micellar formulation for valspodar and assessment of its pharmacokinetics in rat

The aim of this study was to assess the potential of polymeric micelles to solubilize valspodar and modify its pharmacokinetics following intravenous and oral administration in rat. Drug-loaded methoxy poly(ethylene oxide)- b-poly(ε-caprolactone) (PEO- b-PCL) micellar solutions were prepared and administered either intravenously or orally to healthy Sprague–Dawley rats. Plasma pharmacokinetic parameters of valspodar in its polymeric micellar formulation were compared to its clinical formulation, which uses Cremophor EL and ethanol as solubilizing agents. High loading level was achieved for valspodar in PEO- b-PCL leading to an aqueous solubility of 2.8 mg/mL. Following i.v. administration (5 mg/kg), valspodar in the PEO- b-PCL micelles provided significantly higher (∼77%) plasma AUC compared to the Cremophor EL formulation. The PEO- b-PCL micelles also significantly decreased the volume of distribution (Vd ss) and clearance (CL) of valspodar by nearly 49% and 34%, respectively. After oral administration (10 mg/kg), the average C max were similar for both formulations and were both reached at ∼2 h. The plasma unbound fraction of valspodar in the polymeric micellar formulation was significantly lower than control (8.27% versus 14.85%). Our results show that PEO- b-PCL micelles can efficiently solubilize valspodar and favorably modify its pharmacokinetic profile in rat after i.v. administration by decreasing the CL and Vd.

A novel nonsecosteroidal VDR agonist (CH5036249) exhibits efficacy in a spontaneous benign prostatic hyperplasia beagle model

To date, there have been no reports showing the efficacy of nonsecosteroidal vitamin D receptor (VDR) agonists in a benign prostatic hyperplasia (BPH) animal model. To examine the efficacy of CH5036249, a novel nonsecosteroidal VDR agonist, we orally administered the compound at 0.03 μg/kg to a beagle model with spontaneous BPH. Prostate volume was checked by rectal ultrasonic probe periodically during 11 months of administration and the prostate tissues histologically examined. CH5036249 inhibited prostate growth in two out of three dogs compared with vehicle-treated dogs. In the prostate specimens, substantial atrophy of the epithelium was observed in all dogs administered CH5036249. At the dose given, serum calcium levels slightly increased in the CH5036249-treated dogs but stayed within a normal range. We next examined the cell growth inhibition of CH5036249 using human prostate stromal cells and found the cell growth inhibitory activity of CH5036249 to be comparable to that of 1α,25(OH) 2D 3. The bioavailability from oral administration in rats was 95.1% with a t 1/2 of 17.6 h. Both micro-AMES and micronucleus tests were negative. Although the results are still preliminary, we consider the novel nonsecosteroidal VDR agonist CH5036249 to be a possible new drug candidate for the treatment of BPH in humans.

Influence of nicardipine and nifedipine on plasma carvedilol disposition after oral administration in rats

The effect of two kinds of 1,4-dihydropyridine calcium-channel blockers, nicardipine hydrochloride and nifedipine, on the disposition of carvedilol, was studied in rats. Blood samples were assayed for carvedilol levels using solid-phase extraction and high-performance liquid chromatography. The plasma carvedilol concentration was found to be significantly higher, and the area under the concentration-time curve up to 24 h (AUC0-->24) was 6.7 and 3.0 times higher after simultaneous oral administration of 20 mg kg(-1) carvedilol with 40 mg kg(-1) nicardipine hydrochloride, or with 40 mg kg(-1) nifedipine, respectively, than after administration of carvedilol alone. The pharmacokinetic interaction between carvedilol and dihydropyridine calcium-channel blockers is thought to be attributable to vasodilator-induced changes in hepatic first-pass metabolism, inhibition in the absorption barrier by P-glycoprotein and in the metabolism of carvedilol.

Effects of the selective EP4 antagonist, CJ-023,423 on chronic inflammation and bone destruction in rat adjuvant-induced arthritis

Prostaglandin E2 (PGE2) produced by cyclooxygenase (COX) is a potent pro-inflammatory mediator. We have recently discovered CJ-023,423, a highly selective antagonist of EP4 receptors, one of the PGE2 receptors. This agent is suitable for exploring the effects of blocking EP4 receptors following oral administration in rats. In this study, CJ-023,423 was used in rats with adjuvant-induced arthritis (AIA) to investigate the role of the EP4 receptor in chronic inflammation and bone destruction. These effects were compared with those of rofecoxib, a selective COX-2 inhibitor. CJ-023,423 had significant inhibitory effects on paw swelling, inflammatory biomarkers, synovial inflammation and bone destruction in AIA rats. In particular, the inhibitory effect on paw swelling in AIA rats was comparable to that of rofecoxib. These results suggest that PGE2 acting via the EP4 receptor is involved in the development of chronic inflammation and bone destruction, particularly with respect to oedema in AIA rats. This is the first study to confirm the in-vivo effects of EP4 receptor blockade on inflammation and bone destruction in AIA rats with a small-molecule compound.

Toxic isolectins from the mushroom Boletus venenatus

Ingestion of the toxic mushroom Boletus venenatus causes a severe gastrointestinal syndrome, such as nausea, repetitive vomiting, diarrhea, and stomachache. A family of isolectins ( B. venenatus lectins, BVLs) was isolated as the toxic principles from the mushroom by successive 80% ammonium sulfate-precipitation, Super Q anion-exchange chromatography, and TSK-gel G3000SW gel filtration. Although BVLs showed a single band on SDS–PAGE, they were further divided into eight isolectins (BVL-1 to -8) by BioAssist Q anion-exchange chromatography. All the isolectins showed lectin activity and had very similar molecular weights as detected by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS) analysis. Among them, BVL-1 and -3 were further characterized with their complete amino acid sequences of 99 amino acids determined and found to be identical to each other. In the hemagglutination inhibition assay, both proteins failed to bind to any mono- or oligo-saccharides tested and showed the same sugar-binding specificity to glycoproteins. Among the glycoproteins examined, asialo-fetuin was the strongest inhibitor. The sugar-binding specificity of each isolectin was also analyzed by using frontal affinity chromatography and surface plasmon resonance analysis, indicating that they recognized N-linked sugar chains, especially Galβ1 → 4GlcNAcβ1 → 4Manβ1 → 4GlcNAcβ1 → 4GlcNAc (Type II) residues in N-linked sugar chains. BVLs ingestion resulted in fatal toxicity in mice upon intraperitoneal administration and caused diarrhea upon oral administration in rats.

Plasma pharmacokinetics and tissue distribution study of cajaninstilbene acid in rats by liquid chromatography with tandem mass spectrometry

Cajaninstilbene acid (CSA; 3-hydroxy-4-prenyl-5-methoxystilbene-2-carboxylic acid) is a major active constituent of pigeonpea leaves, has been proven to be effective in clinical treatment of diabetes, hepatitis, measles and dysentery. A rapid and sensitive liquid chromatography tandem mass spectrometry (LC–MS/MS) method was developed and validated for the determination of CSA in rat plasma and various tissues (brain, heart, lung, liver, spleen, small intestine and kidney) of rat for the first time. Rat plasma and tissue distribution pre-treated by protein precipitation with acetoacetate was analyzed using LC–MS/MS with an electrospray ionization (ESI) interface, and isoliquiritigenin was used as an internal standard. Chromatographic separation was achieved on a HIQ Sil C 18 column with the mobile phase of water and methanol (9:91, v/v) containing 0.1% formic acid and resulted in a total run time of 10 min. The isocratic elution mode pumped at a flow rate of 1.0 mL/min. The lower limit of quantification (LLOQ) which was 10 ng/mL. The calibration curve was linear from 10 to 6000 ng/mL ( R = 0.9967) for plasma samples and 10 to 6000 ng/mL ( R ≥ 0.9974) for tissue homogenates. The intra- and inter-day assay of precision in plasma and tissues ranged from 0.6% to 6.1% and 1.5% to 6.6%, respectively, and the intra- and inter-day assay accuracy was 93.5–104.6% and 93.3–107.5%, respectively. Recoveries in plasma and tissues ranged from 95.0% to 106.8%. The method was successfully applied in pharmacokinetic and tissue distribution studies of CSA after oral administration to rats. The pharmacokinetics of CSA showed rapid absorption and elimination ( T max, 10.7 ± 0.31 min; t 1/2, 51.40 ± 6.54 min). After oral administration in rats, CSA was rapidly and widely distributed in tissues. High concentrations were found in liver and kidney indicating that CSA was possibly absorbed by liver and eliminated by kidney.

TAK-285, a Novel HER2/EGFR Inhibitor, Penetrates the CNS in Rats with an Intact Blood Brain Barrier (BBB).

Abstract Background: Approximately one third of patients with HER2-overexpressing (HER2+) metastatic breast cancer develop brain metastases. Treatment options for patients whose brain metastases have progressed after radiotherapy are urgently needed. The currently approved HER2-targeted therapies, trastuzumab and lapatinib, have generally shown limited activity against brain metastases, likely due to the limited brain penetration of these drugs. Brain penetration is mediated by multiple factors including drug permeability, tissue binding, and the expression of efflux transporters (P-gp and BCRP) and their interactions with the drug. TAK-285 is a novel, orally active, dual HER2/EGFR inhibitor currently under clinical development. In this nonclinical work, we evaluated the permeability, interactions with efflux transporters, and brain penetration of TAK-285, along with lapatinib and neratinib, using in vitro and animal models.Material and Methods: The first study evaluated the permeability of TAK-285, lapatinib, and neratinib and their interactions with efflux transporters using the Caco-2 cell monolayer system in the absence or presence of efflux pump inhibitors. The second study evaluated brain penetration of TAK-285, lapatinib and neratinib after a single oral administration in rats with an intact BBB.Results: In the Caco-2 cell model, TAK-285 showed high permeability with an efflux ratio of 1.7, indicating it is not a substrate for efflux pumps. The efflux pump inhibitors LY335979 (an inhibitor of P-gp), Ko143 (an inhibitor of BCRP), and GF120918 (an inhibitor of BCRP and P-gp) had no marked effect on the efflux ratio of TAK-285, further confirming that TAK-285 is not a substrate for P-gp and BCRP. Lapatinib and neratinib showed low to medium permeability and appeared to be substrates for P-gp/BCRP in this testing system. In the rat brain penetration study, the brain-to-plasma AUC ratio for total (free and bound) TAK-285, lapatinib, and neratinib was 0.202, 0.0243, and 0.0263, respectively.Discussion: These nonclinical studies showed that, unlike lapatinib and neratinib, TAK-285 is not a substrate for the efflux transporters, P-gp and BCRP. Based on published information, all of the approved receptor tyrosine kinase inhibitors are substrates for efflux transporters. Additionally, in rats with an intact BBB, the brain-to-plasma AUC ratio for TAK-285 was substantially higher than that of lapatinib and neratinib. The AUC ratios observed in this study for lapatinib and neratinib are similar to the proportion of blood volume in the rat brain (ie, outside the CNS) relative to the total rat brain volume. This suggests the actual brain-to-plasma AUC ratio for TAK-285 in rats may be much greater than 8-fold of that of lapatinib and neratinib calculated based on these measured AUC ratios. Consequently, TAK-285 may have a unique role in the treatment of brain lesions in patients with HER2- or EGFR-dependent tumors. Furthermore, TAK-285 may not be subject to drug resistance conferred by efflux transporters. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5098.

Preparation, characterization and in vivo evaluation of bergenin-phospholipid complex

To prepare a bergenin-phospholipid complex (BPC) to increase oral bioavailability of the drug. In order to obtain the acceptable BPC, a spherical symmetric design-response surface methodology was used for process optimization. The influence of reaction medium, temperature, drug concentration and drug-to-phospholipid ratio on the combination percentage and content of bergenin in BPC were evaluated. BPC was then characterized by thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC), ultra-violet (UV) spectroscopy, fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC) and X-ray powder diffraction. The physicochemical properties such as microscopic shape, particle size, zeta-potential, solubility, crystalline form, and hygroscopicity were tested. The pharmacokinetic characteristics and bioavailability of BPC were investigated after oral administration in rats in comparison to bergenin and the physical mixture (bergenin and phospholipids). BPC was successfully prepared under the optimum conditions [temperature=60 degrees C, drug concentration=80 g/L and drug-to-phospholipids ratio=0.9 (w/w)]. The combination percentage was 100.00%+/-0.20%, and the content of bergenin in the complex was 45.98%+/-1.12%. Scanning electron microscopy and transmission electron microscopy of BPC showed spherical particles. The average particle size was 169.2+/-20.11 nm and the zeta-potential was -21.6+/-2.4 mV. The solubility of BPC in water and in n-octanol was effectively enhanced. The C(max) and AUC(0-->infinity) of BPC were increased, and the relative bioavailability was significantly increased to 439% of bergenin. The BPC is a valuable delivery system to enhance the oral absorption of bergenin.