Albendazole Metabolites Research Articles

Application potential of albendazole as an aquatic animal drug based on its safety, efficacy, and residue profiles.

The number of available drugs for treating aquatic animals is insufficient, given the occurrence of a variety of parasites and difficulties in developing appropriate treatments, such as vaccines or immunostimulants. Consequently, repurposing livestock drugs for treating aquatic animals is a viable alternative. Several studies have demonstrated that albendazole (ABZ) is a good anthelmintic for humans and animals such as ruminants, poultry, and honeybees. Therefore, we investigated the toxicological studies, metabolic and residue depletion studies, and efficacy trials of ABZ in aquatic animals to identify its application potential as a drug for aquatic animals. ABZ was depleted within 24h in the muscle tissues of hybrid striped bass, rainbow trout, and tilapia. In muscle tissue with adhering skin obtained from tilapia and largemouth bass, a significant quantity of the amino-sulfone metabolite of ABZ (ABZ-SO2NH2) was present, while no ABZ-SO2NH2 was detected in hybrid striped bass, channel catfish, and patinga. Fish exposed only to high doses of ABZ showed reduced red blood cell counts and hemoglobin levels and increased lymphocytes. Such signs of toxicity have also been observed in human patients and animal studies. At a dose of 100mg/L, ABZ showed 100% efficacy in eels. In addition, albendazole sulfoxide (ABZSO) demonstrated efficacies of 96.1% and 100% in pirapatinga and ray-finned fish, respectively, at a dose 500mg/L. ABZ was also highly effective in treating an intracellular parasite E. hepatopenaei in white shrimp. The application of ABZ in aquatic animals under the low-dose and short-term conditions is considered a reasonable solution to manage parasite infections. The types and residual periods of degradation products differed among fish species, suggesting dissimilar metabolic pathways. With a high demand for new alternative veterinary drugs in aquaculture by fish farmers, this review offers important evidence for considering the use of ABZ in Korean farmed fish, taking food safety issues into account.

Understanding Drug Exposure and Trichuris trichiura Cure Rates: A Pharmacometric Approach for Albendazole-Ivermectin Co-medication in Tanzania and Côte d'Ivoire.

Trichuriasis caused by the human whipworm Trichuris trichiura poses a significant public health concern. Albendazole-ivermectin co-medication is currently the most effective treatment. Studies conducted in Tanzania and Côte d'Ivoire unveiled differences in efficacy for albendazole-ivermectin combination therapy in both countries. A pharmacometrics approach was used to assess co-medication and study population effects on the pharmacokinetics of the two main metabolites of albendazole. An exploratory exposure-efficacy analysis was also carried out to investigate relationships between exposure measures and the egg reduction rate. Pharmacokinetic data from studies in Tanzania and Côte d'Ivoire in adolescents (aged 12-19 years) were included in the pharmacometric analysis. Participants received a single dose of either albendazole 400 mg alone or in combination with ivermectin 200 µg/kg. A pharmacometric analysis was performed to investigate the potential effects of the study population and co-administered ivermectin on the apparent clearance of the metabolites of albendazole. Non-linear mixed-effects modeling was conducted with MonolixSuite 2023R1. The pharmacokinetic exposure measures derived from simulations with individual model parameters were used in the exploratory-exposure response analysis. Pharmacokinetic profiles were best described by a two-compartment model for albendazole sulfoxide and a one-compartment model for albendazole sulfone, with a transit compartment and linear elimination. While no co-medication effect was found, apparent clearance of albendazole sulfoxide (albendazole sulfone) in the Tanzanian study population was 75% (46%) higher than that in the Côte d'Ivoire study population. Exposure-efficacy response analyses indicated that peak concentration and the time-above-exposure threshold were associated with the egg reduction rate. Study population but not co-administered ivermectin showed an effect on apparent clearance of albendazole sulfoxide and albendazole sulfone. Polymorphisms in drug-metabolizing enzymes and host-parasite interaction may explain this result. Difference in drug exposure did not explain the disparate efficacy responses in Tanzania and Côte d'Ivoire. Peak concentration and time-above-threshold were exposure measures associated with the egg reduction rate. Further studies evaluating genetic and resistance patterns in various regions in Africa are warranted.

Albendazole metabolites excretion in human saliva as a biomarker to assess treatment compliance in mass drug administration (MDA) anthelmintic programs.

Soil-transmitted-helminth (STH) infections continue to be a persistent global public health problem. Control strategies for STH have been based on the use of mass drug administration (MDA). Coverage and compliance assessment is critical to understanding the trueeffectiveness of albendazole(ABZ) in those MDA programs.The aims of this work wereto characterize the pattern ofalbendazole and metabolites excretion in human saliva, and to develop a saliva-based biomarker (HPLC drug/metabolite detection)useful to accurately estimate the coverage/compliance in MDA campaigns.The study subjects were 12 healthy volunteers treated with a single oral dose of ABZ (400 mg). Saliva and blood (dried blood spot, DBS) samples were taken previously and between 2 and 72 h post-treatment. The samples were analyzed by HPLC with UV detection, C18 reversed-phase column. ABZ sulphoxide was the main analyte recovered up to 72 h p.t. in blood and saliva. The concentration profiles measured in the blood (DBS samples) were higher (P < 0.05) than those in saliva, however,this ABZ-metabolite was recovered longer in saliva.Thein vivomeasurement of drugs/metabolites in saliva samples from ABZ-treated volunteers offers strong scientific evidence to support the use of saliva as a valid biological sample for assessing compliance in MDA programs.

Dual-emissive Eu(III)-functionalized metal-organic frameworks for visual, rapid, and intelligent sensing of albendazole and albendazole sulfoxide in animal-origin food

Albendazole (ABZ), a benzimidazole-based anthelmintic, is widely used to treat helminth infections. The extensive and improper use of ABZ may cause drug residues in animal-origin food and anthelmintics resistance, which potentially threaten human health. Meanwhile, albendazole sulfoxide (ABZSO), a metabolite of ABZ, also exhibits toxic effects. Therefore, the detection of ABZ and ABZSO in animal-derived food is significantly necessary. Herein, a dual-emission europium fluorescent sensor (EuUHC-30) was rationally designed and constructed. EuUHC-30 exhibits high selectivity and sensitivity towards ABZ and ABZSO with a detection limit of 0.10 and 0.13 μM, respectively. Furthermore, EuUHC-30 was successfully applied for quantification of ABZ and ABZSO in milk and pig kidney, which were verified by HPLC analysis. Moreover, a smartphone-assisted EuUHC-30 fluorescent paper sensor was fabricated for the practical determination of ABZ and ABZSO in real food. Overall, this work provides a visual, rapid, and intelligent method for the detection of ABZ and ABZSO in animal-origin food.

Simultaneous quantitative determination of residues of abamectin, ivermectin, albendazole and its three metabolites in beef and chicken by HPLC-PDA.

Antimicrobial drugs are frequently used in a combination or shuttle way to cope with coinfection of bacteria or parasites and prevent drug resistance, thus the accurate quantification of multiple drug residues in animal-derived foods is crucial to ensure food safety. Here, a simple and efficient high-performance liquid chromatography-photodiode array (HPLC-PDA) method was established for the simultaneous quantitative screening of six common residues of antiparasitic drugs, including abamectin (ABM), ivermectin (IVM), albendazole (ABZ) and the three metabolites of ABZ in beef and chicken. The LODs and LOQs for six target compounds in beef and chicken are determined to be 3.2 to 12.5µg/kg and 9.0 to 30.0µg/kg, respectively. The calibration curves show good linearity (R2≥0.9990) between the peak area and concentration. The recoveries from the fortified blank samples are all above 85.10%. Finally, the applicability of the HPLC-PDA method is successfully demonstrated by the real sample analysis.

Melatonin in Combination with Albendazole or Albendazole Sulfoxide Produces a Synergistic Cytotoxicity against Malignant Glioma Cells through Autophagy and Apoptosis.

Glioblastoma is the most aggressive and lethal brain tumor in adults, presenting diffuse brain infiltration, necrosis, and drug resistance. Although new drugs have been approved for recurrent patients, the median survival rate is two years; therefore, new alternatives to treat these patients are required. Previous studies have reported the anticancer activity of albendazole, its active metabolite albendazole sulfoxide, and melatonin; therefore, the present study was performed to evaluate if the combination of melatonin with albendazole or with albendazole sulfoxide induces an additive or synergistic cytotoxic effect on C6 and RG2 rat glioma cells, as well as on U87 human glioblastoma cells. Drug interaction was determined by the Chou-Talalay method. We evaluated the mechanism of cell death by flow cytometry, immunofluorescence, and crystal violet staining. The cytotoxicity of the combinations was mainly synergistic. The combined treatments induced significantly more apoptotic and autophagic cell death on the glioma cell lines. Additionally, albendazole and albendazole sulfoxide inhibited proliferation independently of melatonin. Our data justify continuing with the evaluation of this proposal since the combinations could be a potential strategy to aid in the treatment of glioblastoma.

Albendazole from ovine excrements in soil and plants under real agricultural conditions: Distribution, persistence, and effects

Albendazole (ABZ), a broad-spectrum anthelmintic drug frequently used in livestock against parasitic worms (helminths), enters the environment mainly via faeces of treated animals left in the pastures or used as dung for field fertilization. To obtain information about the subsequent fate of ABZ, the distribution of ABZ and its metabolites in the soil around faeces along with uptake and effects in plants were monitored under real agricultural conditions. Sheep were treated with a recommended dose of ABZ; faeces were collected and used to fertilize fields with fodder plants. Soil samples (in two depths) and samples of two plants, clover (Trifolium pratense) and alfalfa (Medicago sativa), were collected at distances 0–75 cm from the faeces for 3 months after fertilization. The environmental samples were extracted using QuEChERS and LLE sample preparation procedures. The targeted analysis of ABZ and its metabolites was conducted by using the validated UHPLC-MS method. Two main ABZ metabolites, ABZ-sulfoxide (anthelmintically active) and ABZ-sulfone (inactive), persisted in soil (up to 25 cm from faeces) and in plants for three months when the experiment ended. In plants, ABZ metabolites were detected even 60 cm from the faeces and abiotic stress was observed in the central plants. The considerable distribution and persistence of ABZ metabolites in soil and plants amplify the negative environmental impact of ABZ documented in other studies.

Feeding Management and Albendazole Pharmacokinetics in Pigs.

Albendazole (ABZ) is a methylcarbamate benzimidazole anthelmintic used to control gastrointestinal parasites in several animal species and humans. The type of diet has been identified as a major determinant for ABZ pharmacokinetics in different animal species and humans. The work described here assesses the pattern of the absorption and the systemic availability of ABZ and its metabolites after its oral administration to pigs under different feed management plans. Eighteen pigs (5 months old, local ecotype breeds) were distributed into three experimental groups. In the fasting group, the animals fasted for 8 h prior to treatment. In the pellet + oil and pellet groups, the animals were fed ad libitum with a commercial pelleted-based diet with or without the addition of soya oil. An ABZ suspension was orally administered at 10 mg/kg. Blood samples were taken over the 48 h post-treatment. The plasma samples were analyzed by HPLC. Under the described experimental conditions, the ingestion of the pellet-based diet with or without the soya oil before ABZ treatment did not significantly (p < 0.05) modify the plasma disposition kinetics of the ABZ sulfoxide (ABZSO, the main ABZ metabolite) compared to that observed in the fasting pigs. Both ABZ metabolites (ABZSO and ABZ sulphone) reached similar peak concentrations and systemic exposures in all the experimental groups regardless of the feeding management. However, the addition of oil to the pelleted food enhanced the pattern of ABZ absorption, which was reflected in the higher (p < 0.05) concentration profiles of the active ABZSO metabolite measured between 12 and 48 h post-treatment compared to the pigs fed with the pelleted food alone. Although this effect may not be therapeutically relevant after ABZ administration as a single oral dose, the overall impact of the type and feeding conditions when ABZ is supplemented with food for several days should be cautiously evaluated.

Novel albendazole-glucan particles for enhancing intestinal absorption and improving hepatic targeting.

Glucan particles (GPs) are derived from the Saccharomyces cerevisiae cell wall. The hollow particles composed of β-1,3-D-glucan have been extensively studied in terms of immune regulation and macrophage-targeted drug delivery. Albendazole (ABZ) is a benzimidazole drug with good anti-parasitic activity and is the drug recommended by the World Health Organization for the first-line treatment of hydatid disease. A dynamic light scatterometer, scanning electron microscope, and transmission electron microscope were used to characterize the ABZ-GPs. High-performance liquid chromatography (HPLC), laser scanning confocal microscope (LSCM) and an in vivo small animal imaging system were used to evaluate theability of ABZ-GPs to be recognized by macrophages, whether ABZ-GPs are more readily absorbed and eliminated in the blood than the original ABZ drug in rats, and the ability of ABZ-GPs to target the mouse liver. The ABZ-GPs were successfully constructed to achieve fluorescence, magnetic resonance imagining, and laser confocal microscopy imaging. The glucan shell effectively protects ABZ from enzymatic degradation and from being pumped out in the gastrointestinal tract. The analysis of ABZ and its major metabolite albendazole sulfoxide in the rat plasma and mouse liver showed that compared to the ABZ suspension group, the degradation of ABZ-GPSs in the blood was low, and the targeting of ABZ-GPSs in the liver was significantly enhanced. In the oral treatment of hepatic hydatid disease, GPs can be used as carriers to achieve the targeted transport of ABZ, which in turn can be used for the targeted therapy of liver echinococcosis. Thus, ABZ-GPs may be a promising form of targeted therapy.

Multi-residue methodology for quantification of antiparasitics in hen eggs by LC-MS/MS: development, validation and application to 348 samples from Brazil

Analytical methodology for quantification of 15 antiparasitic drugs and their respective metabolites in laying hen eggs was optimized and validated. The method uses acetonitrile as solvent extraction, sodium chloride for salting-out, low-temperature purification and analysis by LC-MS/MS. A total of 348 egg samples were collected in 11 states of Brazil and 50% of the total samples presented antiparasitic residues, which were albendazole, fipronil, fenbendazole, ivermectin, oxibendazole and mebendazole. A total of 12.4% of the samples were considered non-compliant, and residues quantified in these samples were albendazole, fipronil, and mebendazole. Albendazole was always identified as albendazole sulfone. Only one sample presented fipronil and fipronil sulfone; all others exclusively the sulfone metabolite. Fenbendazole was characterized by the presence of both metabolites: sulfone and sulfoxide. Maximum limits adopted are based on the Normative Instruction 51/2019 of the Brazilian Health Regulatory Agency (ANVISA), but albendazole, fipronil, oxibendazole, ivermectin, and mebendazole do not have their maximum residue level established. In addition, metabolites of albendazole, fipronil and fenbendazole in eggs are not considered in this Instruction.

Secretion into Milk of the Main Metabolites of the Anthelmintic Albendazole Is Mediated by the ABCG2/BCRP Transporter.

Albendazole (ABZ) is an anthelmintic with a broad-spectrum activity, widely used in human and veterinary medicine. ABZ is metabolized in all mammalian species to albendazole sulfoxide (ABZSO), albendazole sulfone (ABZSO2) and albendazole 2-aminosulphone (ABZSO2-NH2). ABZSO and ABZSO2 are the main metabolites detected in plasma and all three are detected in milk. The ATP-binding cassette transporter G2 (ABCG2) is an efflux transporter that is involved in the active secretion of several compounds into milk. Previous studies have reported that ABZSO was in vitro transported by ABCG2. The aim of this work is to correlate the in vitro interaction between ABCG2 and the other ABZ metabolites with their secretion into milk by this transporter. Using in vitro transepithelial assays with cells transduced with murine Abcg2 and human ABCG2, we show that ABZSO2 and ABZSO2-NH2 are in vitro substrates of both. In vivo assays carried out with wild-type and Abcg2-/- lactating female mice demonstrated that secretion into milk of these ABZ metabolites was mediated by Abcg2. Milk concentrations and milk-to-plasma ratio were higher in wild-type compared to Abcg2-/- mice for all the metabolites tested. We conclude that ABZ metabolites are undoubtedly in vitro substrates of ABCG2 and actively secreted into milk by ABCG2.

The induction and inhibition of UDP-glycosyltransferases in Haemonchus contortus and their role in the metabolism of albendazole

Albendazole (ABZ) is an anthelmintic frequently used to treat haemonchosis, a common parasitosis of ruminants caused by the gastrointestinal nematode Haemonchus contortus. This parasite is able to protect itself against ABZ via the formation of inactive ABZ-glycosides. The present study was designed to deepen the knowledge about the role of UDP-glycosyltransferases (UGTs) in ABZ glycosylation in H. contortus. The induction effect of phenobarbital, a classical inducer of UGTs, as well as ABZ and ABZ-sulphoxide (ABZSO, the main active metabolite of ABZ) on UGTs expression and UGT activity toward ABZ was studied ex vivo in isolated adult nematodes. The effect of three potential UGT inhibitors (5-nitrouracil, 4,6-dihydroxy-5-nitropyrimidine and sulfinpyrazone) on ABZ glycosylation was tested. Pre-incubation of nematodes with ABZ and ABZSO led to increased expression of several UGTs as well as ABZ-glycosides formation in subsequent treatment. Phenobarbital also induced UGTs expression, but did not affect ABZ biotransformation. In the nematode's subcellular fraction, sulfinpyrazone inhibited UGT activity toward ABZ, although no effect of other inhibitors was observed. The inhibitory potential of sulfinpyrazone on the formation of ABZ-glycosides was also proved ex vivo in living nematodes. The obtained results confirmed the role of UGTs in ABZ biotransformation in H. contortus adults and revealed sulfinpyrazone as a potent inhibitor of ABZ glycosylation in this parasite. The possible use of sulfinpyrazone with ABZ in combination therapy merits further research.

Determination of Albendazole Metabolite in Livestock Products Using LC-MS/MS

A method for determining albendazole metabolite (metabolite I) in livestock products using LC-MS/MS was proposed. Livestock samples were hydrolyzed with 6 mol/L HCl at 110℃ for an hour and defatted with ethyl acetate and n-hexane (1 : 1, v/v) mixture. Metabolite I was extracted with acetonitrile from the sample, and the extracts were salted out under basic conditions, allowing the acetonitrile layer to separate. The acetonitrile solution was cleaned up using a cartridge column packed with divinylbenzene-N-vinylpyrolidone copolymer bearing sulfo groups. The HPLC separation was conducted on an Inertsil ODS-4 column with a gradient formed from water containing 0.05% (v/v) formic acid and acetonitrile containing 0.05% (v/v) formic acid. To detect metabolite I, tandem mass spectrometry with positive ion electrospray ionization was used. Truenesses (n=5) of metabolite I from cattle meat, fat, liver, and milk spiked at the maximum residue limits or the 0.01 mg/kg were in the range from 83.6 to 97.9%, and the relative standard deviations were from 1.6 to 6.1%.

Aspects of albendazole metabolism in western lowland gorillas (Gorilla gorilla gorilla) compared to humans and other species assessed by HPLC, LC‐MS, and chiral electrokinetic chromatography

AbstractThe benzimidazole anthelmintic drug albendazole becomes metabolized to chiral albendazole sulfoxide, albendazole sulfone, albendazole 2‐aminosulfone, and other metabolites. High‐performance liquid chromatography with UV absorbance and fluorescence detection, liquid chromatography with mass spectrometry, and chiral electrokinetic chromatography were used to analyze albendazole metabolites in extracts of western lowland gorilla (Gorilla gorilla gorilla) plasma of patients with alveolar echinococcosis and the data are compared to those obtained with human patient samples and to those reported for other species in the literature. The data revealed that the albendazole sulfoxide to albendazole sulfone concentration ratio in gorilla plasma is significantly smaller compared to that in samples of men, rats, dogs, and cattle. It is, however, similar to what was observed in sheep and goats. The (+)‐albendazole sulfoxide to (−)‐albendazole sulfoxide enantiomeric ratio in gorilla blood determined by chiral electrokinetic chromatography was found to be &gt;1 which is comparable to what was observed in humans, dogs, sheep, goats, and cattle but different to mice and rats. Furthermore, the electrokinetic chromatography data suggest that small amounts of albendazole 2‐aminosulfone may be present in plasma of gorillas and humans. The data gathered with the various separation‐based assays illustrate the value of technology featuring different analyte separation and detection principles. This is the first account describing aspects of the albendazole metabolism in gorillas.

Proof of the environmental circulation of veterinary drug albendazole in real farm conditions

Anthelmintics, drugs against parasitic worms, are frequently used in livestock and might act as danger environmental microcontaminants. The present study was designed to monitor the possible circulation of common anthelmintic drug albendazole (ABZ) and its metabolites in the real agriculture conditions. The sheep were treated with the recommended dose of ABZ. Collected faeces were used for the fertilization of a field with fodder plants (alfalfa and clover) which served as feed for sheep from a different farm. The selective ultrasensitive mass spectrometry revealed surprisingly high concentrations of active ABZ metabolite (ABZ-sulphoxide) in all samples (dung, plants, ovine plasma, rumen content and faeces). Our results prove for the first time an undesirable permeation of ABZ metabolites from sheep excrement into plants (used as fodder) and subsequently to other sheep in real agricultural conditions. This circulation causes the permanent exposition of the ecosystems and food-chain to the drug and can promote the development of drug resistance in helminths.

New and sensitive HPLC-UV method for concomitant quantification of a combination of antifilariasis drugs in rat plasma and organs after simultaneous oral administration.

A combination treatment comprising ivermectin (IVM), albendazole (ABZ) and doxycycline (DOX) is often prescribed for lymphatic filariasis patients. Nevertheless, there has not been an analytical method established and documented to determine these compounds simultaneously. Herein, we report a new high-performance liquid chromatographic method coupled with a UV detector (HPLC-UV) to quantify these drugs in plasma and organs. This developed analytical method was validated according to the International Conference on Harmonization (ICH) and US Food and Drug Administration (FDA) guidelines. The validated method was successfully employed to analyze IVM, ABZ along with its metabolites (albendazole sulfoxide (ABZ-OX) and albendazole sulfone (ABZ-ON)), and DOX in the plasma and organs of Wistar rats after simultaneous oral administration. An Xselect CSH™ C18 HPLC column was utilized as a stationary phase, with a mobile phase consisting of 0.1% v/v trifluoracetic acid in water and acetonitrile with a run time of 20 min. The calibration curves in biological samples were found to be linear across the concentration range of 0.01-5 μg mL-1 for IVM, ABZ and ABZ metabolites, and 0.025-10 μg mL-1 for DOX with an R value ≥0.998 in each case. The validated method was found to be selective, precise and accurate. Finally, the method developed in this study was deployed to assess the pharmacokinetic profiles and biodistribution of the combination of drugs after oral administration to Wistar rats. The validated HPLC-UV method in this study provides an extensive range of prospective applications for pharmacokinetic-based studies, therapeutic drug monitoring and toxicology.

UDP-Glycosyltransferases and Albendazole Metabolism in the Juvenile Stages of Haemonchus contortus.

The nematode Haemonchus contortus, a gastrointestinal parasite of ruminants, can severely burden livestock production. Although anthelmintics are the mainstay in the treatment of haemonchosis, their efficacy diminishes due to drug-resistance development in H. contortus. An increased anthelmintics inactivation via biotransformation belongs to a significant drug-resistance mechanism in H. contortus. UDP-glycosyltransferases (UGTs) participate in the metabolic inactivation of anthelmintics and other xenobiotic substrates through their conjugation with activated sugar, which drives the elimination of the xenobiotics due to enhanced solubility. The UGTs family, in terms of the biotransformation of commonly used anthelmintics, has been well described in adults as a target stage. In contrast, the free-living juvenile stages of H. contortus have attracted less attention. The expression of UGTs considerably varies throughout the life cycle of the juvenile nematodes, suggesting their different roles. Furthermore, the constitutive expression in a susceptible strain with two resistant strains shows several resistance-related changes in UGTs expression, and the exposure of juvenile stages of H. contortus to albendazole (ABZ) and ABZ-sulfoxide (ABZSO; in sublethal concentrations) leads to the increased expression of several UGTs. The anthelmintic drug ABZ and its primary metabolite ABZSO biotransformation, tested in the juvenile stages, shows significant differences between susceptible and resistant strain. Moreover, higher amounts of glycosidated metabolites of ABZ are formed in the resistant strain. Our results show similarly, as in adults, the UGTs and glycosidations significant for resistance-related differences in ABZ biotransformation and warrant further investigation in their individual functions.

Evaluation of the efficacy of albendazole sulfoxide (ABZ-SO)-loaded chitosan-PLGA nanoparticles in the treatment of cystic echinococcosis in laboratory mice.

Albendazole is known as the drug of choice for medical treatment of cystic echinococcosis (CE). Albendazole sulfoxide (ABZ-SO), as the main active metabolite of albendazole, has low efficacy in the disease due to low water solubility and poor absorptivity. PLGA nanoparticles (NPs) enhance the dissolution of poorly soluble drugs, and chitosan (CS) coating enhances oral drug delivery of NPs. In this study, the efficacy of ABZ-SO-loaded CS-PGLA NPs in the treatment of CE was evaluated in laboratory mice. ABZ-SO-loaded CS-PGLA NPs were prepared by nanoprecipitation and characterized by dynamic light scattering method and scanning electron microscopy. Thirty mice were intraperitoneally infected by 1000 protoscoleces of Echinococcus granulosus. Ten months later, the mice were allocated into 3 groups: groups 1 and 2 were treated with ABZ-SO and ABZ-SO-loaded CS-PGLA NPs, respectively, and the mice in group 3 remained untreated as the control group. The drugs were administered by gavage for 45 days at a daily dose of 10 mg/kg. Finally, all mice were opened and the cysts were collected, counted, weighed, and measured separately. The therapeutic effect of ABZ-SO in the number, weight, and volume of the cysts were not statistically significant compared with those in ABZ-SO-loaded CS-PGLA NPs and the control group. However, the therapeutic effect of ABZ-SO-loaded CS-PGLA NPs in the weight and volume of cysts were statistically significant when compared with that in the control group (p ˂ 0.05). In conclusions, this study revealed that ABZ-SO-loaded CS-PGLA NPs could enhance the therapeutic efficacy of ABZ-SO in the treatment of CE in laboratory mice.

A combined in vitro in-silico approach to predict the oral bioavailability of borderline BCS Class II/IV weak base albendazole and its main metabolite albendazole sulfoxide

The aim of this study was to use a combined in vitro-in silico approach to develop a physiologically based pharmacokinetic model (PBPK) that predicts the bioavailability of albendazole (ABZ), a BCS class II/IV lipophilic weak base, and simulates its main metabolite albendazole sulphoxide (ABZSO) after oral administration of the current marketed dose of 400 mg in the fasted state. In vitro data was collected from solubility and dissolution tests performed with biorelevant media and transfer tests were carried out to evaluate the supersaturation and precipitation characteristics of ABZ upon gastric emptying. These in vitro results were used as biopharmaceutical inputs together with ABZ physicochemical properties including also permeability and in vitro metabolism data and information gathered from different clinical trials reported in the literature, were used to enable PBPK models to be developed using GastroPlus™ (version 9.7). As expected for this weak base with pKa = 3.6, ABZ exhibited a pronounced pH dependent solubility, with the solubility and extent of dissolution being greater at gastric pH and dropping significantly in the intestinal environment suggesting supersaturation and precipitation upon gastric emptying, which was confirmed by the transfer model experiments. PBPK models were set up for heathy volunteers using a full PBPK modeling approach and by implementing dynamic fluid volumes in the ACAT gut physiology in GastroPlus™. When coupling in vitro data (solubility values, dissolution rate and precipitation rate constant, etc.) for ABZ and with fitted values for the Vdss and liver systemic clearance of the sulfoxide metabolite to the PBPK model, the simulated profiles successfully predicated plasma concentrations of ABZ at 400 mg dose and simulated ABZSO at different ABZ dose levels and with different study populations, indicating the usefulness of combing in vitro biorelevant tools with PBPK modeling for the accurate prediction of ABZ bioavailability. The results obtained in this study also helped confirm that ABZ behaves as a BCS class IV compound.

The Identification of Metabolites and Effects of Albendazole in Alfalfa (Medicago sativa)

Albendazole (ABZ), a widely used anthelmintic drug, enters the environment mainly via livestock excrements. To evaluate the environmental impact of ABZ, the knowledge of its uptake, effects and metabolism in all non-target organisms, including plants, is essential. The present study was designed to identify the metabolic pathway of ABZ and to test potential ABZ phytotoxicity in fodder plant alfalfa, with seeds and in vitro regenerants used for these purposes. Alfalfa was chosen, as it may meet manure from ABZ-treated animals in pastures and fields. Alfalfa is often used as a feed of livestock, which might already be infected with helminths. The obtained results showed that ABZ did not inhibit alfalfa seed germination and germ growth, but evoked stress and a toxic effect in alfalfa regenerants. Alfalfa regenerants were able to uptake ABZ and transform it into 21 metabolites. UHPLC-MS/MS analysis revealed three new ABZ metabolites that have not been described yet. The discovery of the parent compound ABZ together with the anthelmintically active and instable metabolites in alfalfa leaves shows that the contact of fodder plants with ABZ-containing manure might represent not only a danger for herbivorous invertebrates, but also may cause the development of ABZ resistance in helminths.