Absolute Bioavailability In Rats Research Articles

Drug-like properties of serial phenanthroindolizidine alkaloid compounds: ADMET characteristic prediction and validation

Phenanthroindolizidine alkaloids (PAs) are a series of compounds that have been isolated from traditional herbal medicines and have significant therapeutic potential, such as anti-arthritic, anti-viral, anti-inflammatory, and anti-glioma effects in vitro and in vivo. This study aimed to predict the absorption, distribution, metabolism, excretion, and toxicity (ADMET) characteristics of 44 compounds in silico and to verify the ADMET characteristics. The 2-dimensional structures of these compounds were generated using ChemDraw and the characteristics were predicted using ADMET Predictor™ software. Key characteristics, such as pK a, logP/logD, solubility, permeability, absolute bioavailability in rats, and preliminary toxicity, were measured on some typical compounds to verify the accuracy of the prediction results. The results showed that ADMET predicts physicochemical and biological properties quickly and accurately for PAs. PAs are biopharmaceutics classification system (BCS) class IV compounds with low bioavailability. Moreover, these compounds have higher lipophilicity and are easily distributed into the brain after oral administration to treat brain diseases. However, some of these compounds exhibited colonic toxicity. To improve the drug-like availability of these compounds, more in-depth research should be conducted on drug delivery systems.

Application of Oil-in-Water Cannabidiol Emulsion for the Treatment of Rheumatoid Arthritis.

Introduction: Rheumatoid arthritis (RA) is a chronic autoimmune disease with unknown cause. It mainly affects joints and, without proper treatment, negatively impacts their movement, causes painful deformities, and reduces the patients' quality of life. Current treatment options consist of various types of disease-modifying antirheumatic drugs (DMARDs), however 20-30% of patients are partially resistant to them. Therefore, development of new drugs is necessary. Possible option are compounds exhibiting their action via endocannabinoid system, which plays an important role in pain and inflammation modulation. One such compound - cannabidiol (CBD) has already been shown to attenuate synovitis in animal model of RA in in vivo studies. However, it has low bioavailability due to its low water solubility and lipophilicity. This issue can be addressed by preparation of a lipid containing formulation targeting lymphatic system, another route of absorption in the body. Materials and Methods: CBD-containing emulsion was prepared by high-shear homogenization and its droplet size distribution was analysed by optical microscopy. The relative oral bioavailability compared to oil solution as well as total availability of CBD were assessed in a cross-over study in rats and absorption of CBD via lymphatic system was observed. The effect of CBD on the animal model of RA was determined. Results: Compared to oil solution, the emulsion exhibited higher absolute oral bioavailability. Significant lymphatic transport of CBD was observed in all formulations and the concentrations in lymph were calculated. The therapeutic effect of CBD on RA was confirmed as an improvement in clinical symptoms as well as morphological signs of disease activity were observed during the study. Conclusion: In this work, we prepared a simple stable emulsion formulation, determined the pharmacokinetic parameters of CBD and calculated its absolute bioavailability in rats. Moreover, we successfully tested the pharmaceutical application of such a formulation and demonstrated the positive effect of CBD in an animal model of RA.

Pharmacokinetics of niazirin from Moringa oleifera Lam in rats by UPLC‐MS/MS: Absolute bioavailability and dose proportionality

AbstractNiazirin is a nitrile glycoside isolated from the pods and leaves of Moringa oleifera and possesses antidiabetic activity. However, its pharmacokinetic properties have not been well studied yet. The present study aims to establish a specific, rapid, and simple method for the determination of niazirin in rat plasma and apply it to evaluate its absolute bioavailability and dose proportionality. MS/MS detection was performed in multiple reaction monitoring modes with negative electrospray ionization. The precursor–product ion transitions were m/z 278.1 [M‐H]− → 130.8 for niazirin and m/z 316.9 [M‐H]− → 271.0 for IS. The intra‐ and inter‐day precision (RSD) was <11.53% and the accuracy (RE) ranged from 6.20% to 9.68%. The extraction recoveries ranged from 87.92% to 91.82%. Absolute bioavailability in rats was assessed by comparing pharmacokinetic results after the oral (5, 20, and 40 mg/kg) and intravenous (5 mg/kg) administration. The results indicated that the absolute bioavailability of niazirin in rats was 46.78%, 52.61%, and 48.28%, respectively, and the equations of AUC0−∞ and Cmax at the three doses were y = 177.39x + 99.716 (r2 = 0.9962), and y = 63.152x + 19.531 (r2 = 0.9961), respectively. The study provides a scientific basis for safety evaluation and new clinical research on niazirin.

Anti-fibrosis attributes: UHPLC-MS/MS-based pharmacokinetics profiling of a novel autotaxin inhibitor with excellent in vivo efficacy in rat.

3,4-Difluorobenzyl(1-ethyl-5-(4-((4-hydroxypiperidin-1-yl)-methyl)thiazol-2-yl)-1H-indol-3-yl)carbamate (NAI59), a small molecule with outstanding therapeutic effectiveness to anti-pulmonary fibrosis, was developed as an autotaxin inhibitor candidate compound. To evaluate the pharmacokinetics and plasma protein binding of NAI59, a UPLC-MS/MS method was developed to quantify NAI59 in plasma and phosphate-buffered saline. The calibration curve linearity ranged from 9.95 to 1990.00ng/mL in plasma. The accuracy was -6.8 to 5.9%, and the intra- and inter-day precision was within 15%. The matrix effect and recovery, as well as dilution integrity, were within the criteria. The chromatographic and mass spectrometric conditions were also feasible to determine phosphate-buffered saline samples, and it has been proved that this method exhibits good precision and accuracy in the range of 9.95-497.50ng/mL in phosphate-buffered saline. This study is the first to determine the pharmacokinetics, absolute bioavailability, and plasma protein binding of NAI59 in rats using this established method. Therefore, the pharmacokinetic profiles of NAI59 showed a dose-dependent relationship after oral administration, and the absolute bioavailability in rats was 6.3%. In addition, the results of protein binding showed that the combining capacity of NAI59 with plasma protein attained 90% and increased with the increase in drug concentration.

Pharmacokinetics, tissue distribution and excretion study of trans-resveratrol-3-O-glucoside and its two metabolites in rats

BackgroundTrans-resveratrol-3-O-glucoside (TRG), isolated from the Chinese traditional herbal medicine Huzhang, has been shown to have a wide range of pharmacological benefits. PurposeThe aim of this study is to investigate the pharmacokinetics, tissue distribution and excretion of TRG and its metabolites, (TRN (trans-resveratrol-3-O-glucuronide) and TR (trans-resveratrol)), following a single intragastric (i.g.) administration of TRG in rats. Study designTo evaluate the pharmacokinetic properties of TRG, TRN and TR, groups of rats were administrated a single i.g. dose of either 75, 150 or 300 mg/kg TRG. The absolute bioavailability of TRG was estimated from the ratios of AUC0-∞ values for oral and intravenous administration. Tissue distributions of TRG, TRN and TR in rats were investigated following a single i.g. administration to four groups at 150 mg/kg dosage of TRG. For urinary, fecal and biliary excretion study, TRG, TRN and TR excretions were recovered from a group of rats administered a single i.g. dose of 150 mg/kg TRG. MethodsThe levels of TRG, TRN and TR in plasma, tissues, bile, urine and feces were measured by a rapid and sensitive LC-UV method. The precision was below 10.0%, and the accuracy was within ±9.9% for TRG, TRN and TR. ResultsThe concentrations of TRN were markedly higher than those of TRG and TR in plasma, urine and bile. TRG, TRN and TR showed linear dynamics in dose range of 75–300 mg/kg TRG. TRG had poor absolute bioavailability in rats. The major distribution tissues of TRG, TRN, and TR in rats were in the digestive tract. TRG, TRN and TR were all eliminated from tissues quickly. TRG was mostly excreted via the renal route in the form of TRN, which accounted for 52.8% of the administered dose up to 72 h. ConclusionFollowing a single i.g. administration to rats TRG was easily absorbed and rapidly converted to the metabolites TR and TRN. These metabolites were found to be mainly excreted by the kidneys.

Pharmacokinetics, tissue distribution and plasma protein binding study of SM-1, a novel PAC-1 derivative

As a PAC-1 derivative, SM-1 exhibts a promising antitumour property. To better understand the relationship between the drug concentrations and pharmacological effects, both liquid chromatography coupled with tandem mass spectrometry and high performance liquid chromatography methods were developed and validated in the work. Those methods were then applied to the pharmacokinetics (PK), tissue distribution and plasma protein binding (PPB) studies of SM-1. As a results, the proposed methods were demonstrated to be accurate, precise and stable for the analysis of the SM-1 in plasma and tissue samples. Meanwhile, the PK parameters of SM-1 showed that SM-1 had good PK properties. SM-1 had good absorption in the body, with 59.01% of the absolute bioavailability in rats and 55.63% of that in dogs. SM-1 rapidly distributed to all tissues, with the highest distribution in the lung and less in the brain and muscle. The PPB rates in rat plasma, dog plasma, and human plasma were 91.1%, 91.2%, and 90.7%, respectively. These good PK properties will contribute SM-1 to be a promising anti-tumour candidate. These results also provide insights into the further pharmacological investigation of SM-1.

A UPLC/MS/MS method for determination of protosappanin B in rat plasma and its application of a pharmacokinetic and bioavailability study.

Caesalpinia sappan L. is a traditional medicinal plant which is used for promoting blood circulation and cerebral apoplexy therapy in China. Previous reports showed that the extracts of Caesalpinia sappan L. could exert vasorelaxant activity and anti-inflammation activity. Protosappanin B is a major constituent of C. sappan L., and showed several important bioactivities. The separation was achieved by an Acquity UPLC BEH Symmetry Shield RP18 column (1.7 μm, 2.1 × 100 mm) column with the gradient mobile phase consisting of 5 mm ammonium acetate aqueous solution and acetonitrile. Detection was carried out by using negative-ion electrospray tandem mass spectrometry via multiple reaction monitoring. Plasma samples were preprocessed by an extraction with ethyl acetate, and apigenin was used as internal standard. The current UPLC-MS/MS assay was validated for linearity, accuracy, intraday and interday precisions, stability, matrix effects and extraction recovery. After oral and intravenous administration, the main pharmacokinetic parameters were as follows: peak concentrations, 83.5 ± 46.2 and 1329.6 ± 343.6 ng/mL; areas under the concentration-time curve, 161.9 ± 69.7 and 264.9 ± 56.3 μg h/L; and half-lives, 3.4 ± 0.9 and 0.3 ± 0.1 h, respectively. The absolute bioavailability in rats of protosappanin B was 12.2%. The method has been successfully applied to a pharmacokinetic and bioavailability study of protosappanin B in rats.

Utilization of Microemulsions from Rhinacanthus nasutus (L.) Kurz to Improve Carotenoid Bioavailability.

Carotenoids have been known to reduce the risk of several diseases including cancer and cardiovascular. However, carotenoids are unstable and susceptible to degradation. Rhinacanthus nasutus (L.) Kurz (R. nasutus), a Chinese medicinal herb rich in carotenoids, was reported to possess vital biological activities such as anti-cancer. This study intends to isolate carotenoids from R. nasutus by column chromatography, identify and quantify by HPLC-MS, and prepare carotenoid microemulsions for determination of absolute bioavailability in rats. Initially, carotenoid fraction was isolated using 250 mL ethyl acetate poured into an open-column packed with magnesium oxide-diatomaceous earth (1:3, w/w). Fourteen carotenoids including internal standard β-apo-8′-carotenal were resolved within 62 min by a YMC C30 column and gradient mobile phase of methanol-acetonitrile-water (82:14:4, v/v/v) and methylene chloride. Highly stable carotenoid microemulsions were prepared using a mixture of CapryolTM90, Transcutol®HP, Tween 80 and deionized water, with the mean particle being 10.4 nm for oral administration and 10.7 nm for intravenous injection. Pharmacokinetic study revealed that the absolute bioavailability of carotenoids in microemulsions and dispersion was 0.45% and 0.11%, respectively, while a much higher value of 6.25% and 1.57% were shown for lutein, demonstrating 4-fold enhancement in bioavailability upon incorporation of R. nasutus carotenoids into a microemulsion system.

Pharmacokinetics of isochlorgenic acid C in rats by HPLC-MS: Absolute bioavailability and dose proportionality

Ethnopharmacological relevanceIsochlorgenic acid C (IAC), one of the bioactive compounds of Lonicera japonica, exhibited diverse pharmacological effects. However, its pharmacokinetic properties and bioavailability remained unresolved. Aim of the studyTo determine the absolute bioavailability in rats and the dose proportionality on the pharmacokinetics of single oral dose of IAC. Materials and methodsA validated HPLC-MS method was developed for the determination of IAC in rat plasma. Plasma concentration versus time data were generated following oral and intravenous dosing. The pharmacokinetic analysis was performed using DAS 3.0 software analysis. Absolute bioavailability in rats was determined by comparing pharmacokinetic data after administration of single oral (5, 10 and 25mgkg−1) and intravenous (5mgkg−1) doses of IAC. The dose proportionality of AUC(0-∞) and Cmax were analyzed by linear regression. ResultsExperimental data showed that absolute oral bioavailability of IAC in rats across the doses ranged between 14.4% and 16.9%. The regression analysis of AUC(0-∞) and Cmax at the three doses (5, 10 and 25mgkg−1) indicated that the equations were y=35.23x+117.20 (r=0.998) and y=121.03x+255.74 (r=0.995), respectively. ConclusionsA new HPLC-MS method was developed to determine the bioavailability and the dose proportionality of IAC. Bioavailability of IAC in rats was poor and both Cmax and AUC(0-∞) of IAC had a positive correlation with dose. Evaluation of the pharmacokinetics of IAC will be useful in assessing concentration-effect relationships for the potential therapeutic applications of IAC.

Preclinical pharmacokinetics, tissue distribution and excretion studies of a novel anti-candidal agent-thiosemicarbazide derivative of isoniazid (TSC-INH) by validated UPLC–MS/MS assay

A simple and sensitive UPLC–MS/MS assay was developed and validated for rapid determination of thiosemicarbazide derivative of isoniazid (TSC-INH), a potent anti-candidal agent in rat plasma, tissues, urine and feces. All biological samples were prepared by protein precipitation method using celecoxib as an internal standard (IS). Chromatographic separation was achieved on Acquity BEH™ C18 (50×2.1mm, 1.7μm) column using gradient mobile phase of acetonitrile and water (containing 0.1% formic acid) at flow rate of 0.3mL/min. The MRM transitions were monitored at m/z 305.00→135.89 for TSC-INH and m/z 380.08→316.03 for IS in ESI negative mode. All validation parameter results were within the acceptable range described in guideline for bioanalytical method validation. The pharmacokinetic study showed that the compound TSC-INH was orally active with 66% absolute bioavailability in rats. It was rapidly absorbed with peak plasma concentration of 1985.92ng/mL achieved within 1h after single oral dose (10mg/kg) administration. TSC-INH exhibited rapid distribution across the body with highest levels in liver and lungs. Penetration in brain tissues suggests that TSC-INH crossed the blood brain barrier. Only 5.23% of the orally administered drug was excreted as unconverted form in urine and feces implying that TSC-INH was metabolized extensively before excretion. With the preliminary knowledge of in vivo pharmacokinetics and disposition properties, this study will be beneficial for further development of compound TSC-INH in future studies.

Preclinical Pharmacokinetic Evaluation of β-Lapachone: Characteristics of Oral Bioavailability and First-Pass Metabolism in Rats.

β-Lapachone has drawn increasing attention as an anti-inflammatory and anti-cancer drug. However, its oral bioavailability has not been yet assessed, which might be useful to develop efficient dosage forms possibly required for non-clinical and clinical studies and future market. The aim of the present study was thus to investigate pharmacokinetic properties of β-lapachone as well as its first-pass metabolism in the liver, and small and large intestines after oral administration to measure the absolute bioavailability in rats. A sensitive HPLC method was developed to evaluate levels of β-lapachone in plasma and organ homogenates. The drug degradation profiles were examined in plasma to assess the stability of the drug and in liver and intestinal homogenates to evaluate first-pass metabolism. Pharmacokinetic profiles were obtained after oral and intravenous administration of β-lapachone at doses of 40 mg/kg and 1.5 mg/kg, respectively. The measured oral bioavailability of β-lapachone was 15.5%. The considerable degradation of β-lapachone was seen in the organ homogenates but the drug was quite stable in plasma. In conclusion, we suggest that the fairly low oral bioavailability of β-lapachone may be resulted from the first-pass metabolic degradation of β-lapachone in the liver, small and large intestinal tracts and its low aqueous solubility.

Determination of larotaxel and its metabolites in rat plasma by liquid chromatography–tandem mass spectrometry: Application for a pharmacokinetic study

A sensitive and reliable high-performance liquid chromatography-mass spectrometry (LC-MS/MS) method was developed and validated for determination of larotaxel (LTX) and its active metabolites (M1, M2 and M3) in rat plasma. The analytes were extracted by one-step protein precipitation and separated on a Capcell pak C18 column (2.0 mm × 100 mm; 2 μm; Shiseido) using methanol-water as mobile phase at a flow rate of 0.2 mL min(-1) in gradient mode. The method was validated over the concentration range of 2.5-1250 ng mL(-1) for LTX and 1.0-500 ng mL(-1) for M1, respectively, while M2 and M3 were monitored semi-quantitatively and quantified as M1 equivalents. Intra- and inter-day accuracy and precision were within the acceptable limits of less than 15% at all concentrations. Coefficients of correlation (r) for the calibration curves were more than 0.99 for all analytes. The quantitation method was successfully applied for simultaneous estimation of LTX and its metabolites in a pharmacokinetic study after oral administration at different doses of 10, 20, and 40 mg/kg and intravenous administration at the dose 10 mg/kg to Wistar rats, respectively. The results indicated that larotaxel has linear pharmacokinetic characteristics in rats after oral administration and its absolute bioavailability in rats was 12.24%.

Physicochemical characterization and in vivo evaluation of solid self-nanoemulsifying drug delivery system for oral administration of docetaxel

To formulate a self-nanoemulsifying drug delivery system (SNEDDS) for the oral administration of docetaxel as an alternative to commercial docetaxel-loaded injectable products, it was prepared by spray-drying an aqueous solution containing liquid SNEDDS and colloidal silica. Its physicochemical properties and oral bioavailability were investigated compared to a clear docetaxel solution administered intravenously or orally to rats. In the docetaxel-loaded solid SNEDDS prepared with colloidal silica, the liquid SNEDDS composed of Capryol 90, Cremophore EL and Transcutol HP (45/35/20, volume ratio) was absorbed inside the pores of carriers, and docetaxel was present in a changed amorphous state. The solid SNEDDS with 3.3% (w/v) docetaxel produced nanoemulsions, and showed about 12.5% absolute bioavailability in rats. Thus, this solid SNEDDS may be a potential candidate for oral pharmaceutical product with improved oral bioavailability of docetaxel.

Pharmacokinetics and tissue distribution of schizonepetin in rats

Schizonepetin, a natural monoterpene from Herba Schizonepetae, is a potential antiviral agent. In this paper, a simple, rapid and sensitive HPLC-UV method was first developed and validated for the determination of schizonepetin in rat plasma and tissue homogenates after oral and intravenous administration. The results showed that schizonepetin was absorbed and eliminated rapidly, and its oral absolute bioavailability in rats achieved about 75%. The drug distributed widely in various tissues of rats, and had no long-term accumulation in vivo. The research provides reliable scientific data for designing drug treatment regimens of schizonepetin.