Albendazole Sulphone Research Articles

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.

Depletion study and estimation of the withdrawal period for albendazole in tambaqui (Colossoma macropomum) parasitised by acanthocephalan (Neoechinorhynchus buttnerae) treated with albendazole-containing feed

ABSTRACT This study provides the first data related to albendazole (ABZ) and its main metabolites [albendazole sulphoxide (ABZSO), albendazole sulphone (ABZSO2), and albendazole-2-amino sulphone (ABZ-2-NH2-SO2)] residue depletion in tambaqui (Colossoma macropomum) parasitised by acanthocephalan (Neoechinorhynchus buttnerae). The ABZ withdrawal period was also calculated. The fish received a daily dose of 10 mg ABZ kg−1 body weight (b.w.) via medicated feed for 34 days. Samples of target tissue (muscle plus skin in natural proportions) were collected 24, 48, 72, 120, 168, 240, and 336 h after the end of ABZ administration. The quantitation of ABZ residues and its metabolites in the target tissue was performed using a validated ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) analytical method. After treatment, ABZ in the target tissue was rapidly metabolised over time, and ABZSO was the most persistent metabolite and was shown to be at the highest levels in the target tissue. Considering the maximum residue limit (MRL) established by Codex Alimentarius in the muscle (100 μg kg−1, species not specified), a withdrawal period of 4 days (112 °C-day) was estimated for the total residue (sum of ABZ and its metabolite residues). Considering data reported in the literature and data obtained in this study, it is suggested that the total residue be considered as marker residue to be adopted for fish in the legislative framework.

Combination of bioactive phytochemicals and synthetic anthelmintics: In vivo and in vitro assessment of the albendazole-thymol association

The search of novel strategies for anthelmintic control is a crucial need considering the widespread increase in resistant parasitic populations in livestock. Bioactive phytochemicals may contribute to improve parasite control by enhancing the effect of existing anthelmintic drugs. The aim of the current work was to evaluate the in vivo and in vitro pharmaco-chemical interaction and the in vivo efficacy of the combination of albendazole (ABZ) with thymol (TML) in lambs naturally infected with resistant gastrointestinal nematodes. Thirty (30) lambs were allocated into three experimental groups. Each group was treated orally with either ABZ (5 mg/kg), TML (150 mg/kg, twice every 24 h) or the co-administration of both compounds. Blood samples were collected between 0 and 51 h post-treatment and TML, ABZ and its metabolites were measured by HPLC. Individual faecal samples were collected at days -1 and 14 post-treatment to perform the faecal egg count reduction test. Additionally, the effect of TML on the sulphoreduction and sulphonation of ABZ sulphoxide was assessed in vitro using ruminal content and liver microsomes, respectively. The metabolism of TML in the ruminal content was very low and the monoterpene exhibited a low degree of association with the particulate phase of the ruminal content. No changes in the pharmacokinetic behavior of ABZ sulphoxide were observed in the presence of the natural product (TML). In contrast, the ABZ sulphone Cmax and AUC were lower (P 0.002 and 0.001 respectively) in the co-administered animals (0.16 ± 0.07 μg/mL and 3.63 ± 1.21 μg.h/mL) compared with those that received ABZ alone (0.45 ± 0.15 μg/mL and 9.50 ± 2.84 μg.h/mL). TML was detected in the bloodstream between 1 and 48 h post-treatment, which indicates the time of target nematodes being exposed to the bioactive monoterpene. However, the in vivo efficacy of TML was 0% and the presence of this terpene did not increase the efficacy of ABZ. The presence of TML significantly inhibited the ruminal sulphoreduction (P 0.001) and the hepatic sulphonation (P 0.001) of ABZ sulphoxide. These observations point out that in vivo pharmaco-parasitological studies are relevant to corroborate the adverse kinetic/metabolic interactions and the efficacy of bioactive natural products combined with synthetic anthelmintics.

Food safety evaluation for the use of albendazole in fish: residual depletion profile and withdrawal period estimation

ABSTRACTDue to the lack of drugs regulated for aquaculture, we have evaluated the use of albendazole (ABZ) – a potential drug to be regulated for fish – under food safety perspectives assessing the depletion profile of ABZ and its main metabolites (albendazole sulphoxide – ABZSO, albendazole sulphone – ABZSO2 and albendazole amino sulphone – ABZ-2-NH2SO2) in fish fillets (muscle and skin) after single dose oral administration of 10 mg ABZ kg-1 body weight. For the drug administration, a suitable procedure for ABZ incorporation into fish feed was employed, obtaining good homogeneity of ABZ concentration among feed pellets (CV<4.1%) and low drug leaching when medicated feed remained in the water for up to 60 min (<2.7%). After medication, fish were euthanised at 8, 12, 24, 48, 72, 96 and 120 h and fillets collected. Depletion studies in various fish species (patinga and tilapia) were conducted simultaneously, under water temperature at 30.4 ± 0.3 °C and pH 6.8 ± 0.1. The highest concentrations for the sum of residues (ABZ, ABZSO, ABZSO2 and ABZ-2-NH2SO2) in fish fillet were 1210 ng g-1 in patinga and 637 ng g−1 in tilapia. Under the employed rearing conditions, the obtained results did not indicate a requirement for a minimum withdrawal period to be proposed for tilapia considering the maximum residue limit of 100 µg g−1, since the determined residual concentration was <LOQ (10 ng g−1) from 24 h post medication treatment. For patinga, the estimated minimum withdrawal period was 3 days. With the well-recognised demands for new alternative veterinary drugs for aquaculture use by fish farmers, this study offers important evidence for consideration of ABZ use in tilapia and patinga taking into account food safety issues.

Effect of cooking on the stability of veterinary drug residues in chicken eggs

ABSTRACTThe available information on drug residue stability in chicken egg is scarce. The objective of this study was to evaluate the stability of drug residues in egg under different traditional cooking procedures. Fresh eggs were spiked with different drug concentrations of albendazole (ABZ) and its albendazole sulphoxide (ABZSO) and albendazole sulphone (ABZSO2) metabolites; flubendazole (FLBZ) and its reduced flubendazole (R-FLBZ) and hydrolyzed flubendazole (H-FLBZ) metabolites; amoxicillin (AMX); and enrofloxacin (EFX) and its ciprofloxacin (CFX) metabolite. The egg samples were cooked in different ways, namely, boiling, microwaving, and omelette making. Drug residue concentrations in egg were quantified by HPLC with UV or fluorescence detectors. ABZ and ABZSO concentrations in egg were not affected by boiling and microwaving, while the omelette processing significantly reduced these molecules. Residues of ABZSO2 in egg were stable or increased after all cooking procedures. In contrast, FLBZ and its metabolites FLBZ-H and FLBZ-R residues in egg decreased after all treatments. The residue concentration quantified for EFX and CFX did not show significant changes after any cooking method. AMX residues were unstable, with extremely significant drug reduction after all cooking processes. Conventional methods of egg cooking cannot be considered a tool to eliminate all veterinary drug residues.

A Novel, Quick Column Switching RP-HPLC Guided Metabolite Profiling of Albendazole-Praziquantel in Rat Plasma: Designing New Combination Dosage Regimen with Higher Therapeutic Window

Background: In order to combat neurocysticercosis, effective and novel Fixed Dose Drug Combinations (FDC) of combination dosage regimens have been always under trial; with Albendazole (ABZ) and Praziquantel (PZQ) combination being one of them. Such outcome is basically dependent on the pharmacokinetic profiling of their metabolites such as Albendazole Sulphoxide (ABZSO, active), Albendazole Sulphone (ABZSO2, inactive) and PZQ-TRANS; followed by their back extrapolations to suggest a safe, however potent dosage regimen. Objective: Development of a novel, rapid yet sensitive column switching RP-HPLC method for routine estimation of the aforementioned drugs and metabolites. The improved dosage version in combination is also targeted. Methods: Pooling rat plasma, with column-switch, parent Albendazole-Praziquantel combination was estimated at 225 nm using Enable C-18G column, whereas Albendazole Sulphone and Sulphoxide were estimated using Phenomenex C-18 Luna column at 290 nm. Results: The method showed high accuracy recovering 92~113% of the metabolite or drugs with LOQ as low as 5~50 ng µL-1. Moreover, administration of ABZ-PZQ combination revealed about 3 times slower elimination of active ABZSO than by solitary administration of ABZ. The former also achieved higher Cmax (77.8078 µg mL-1) compared to the latter (69.685 µg mL-1). Also, ABZSO t1/2 in the former has been estimated as 4.25 h compared to 1.38 h of the latter indicating slower ABZSO metabolism in combination therapy than the solo one. Conclusion: The improved pharmacokinetics data could be attributed to the synergistic effect of ABZ and PZQ with each other. This has led to the designing of a novel safe ABZ-PZQ combination dosage regimen for therapeutic applications. Keywords: Albendazole, Albendazole Sulphoxide, Albendazole Sulphone, Praziquantel, HPLC–UV, Column Switch.

Assessment of serum pharmacokinetics and urinary excretion of albendazole and its metabolites in human volunteers.

BackgroundSoil Transmitted Helminth (STH) infections negatively impact physical and mental development in human populations. Current WHO guidelines recommend morbidity control of these infections through mass drug administration (MDA) using albendazole (ABZ) or mebendazole. Despite major reductions in STH associated morbidity globally, not all programs have demonstrated the expected impact on prevalence of parasite infections. These therapeutic failures may be related to poor programmatic coverage, suboptimal adherence or the exposure of parasites to sub-therapeutic drug concentrations. As part of the DeWorm3 project, we sought to characterize the serum disposition kinetics and pattern of urinary excretion of ABZ and its main metabolites ABZ sulphoxide (ABZSO) and ABZ sulphone (ABZSO2) in humans, and the assessment of the duration and optimal time point where ABZ and/or its metabolites can be measured in urine as an indirect assessment of an individual’s adherence to treatment.Methodology/Principal findingsConsecutive venous blood and urine samples were collected from eight (8) human volunteers up to 72 h post-ABZ oral administration. ABZ/metabolites were quantified by HPLC. The ABZSO metabolite was the main analyte recovered both in serum and urine. ABZSO Cmax in serum was 1.20 ± 0.44 μg/mL, reached at 4.75 h post-treatment. In urine, ABZSO Cmax was 3.24 ± 1.51 μg/mL reached at 6.50 h post-ABZ administration.Conclusion/SignificancePharmacokinetic data obtained for ABZ metabolites in serum and urine, including the recovery of the ABZ sulphoxide derivative up to 72 h in both matrixes and the recovery of the amino-ABZ sulphone metabolite in urine samples, are suggesting the possibility of developing a urine based method to assess compliance to ABZ treatment. Such an assay may be useful to optimize ABZ use in human patients.Trial registrationClinicalTrials.gov NCT03192449.

Efficacy of pharmacokinetic interactions between piperonyl butoxide and albendazole against gastrointestinal nematodiasis in goats.

To test the hypothesis that modulation of hepatic microsomal sulphoxidation and sulphonation by the cytochrome P450 inhibitor piperonyl butoxide could increase bioavailability of albendazole, the present study was undertaken to understand the pharmacokinetics of albendazole in goats at a dose of 7.5mgkg-1 body weight with and without co-administration with piperonyl butoxide at 63.0mgkg-1 body weight. Plasma albendazole sulphoxide metabolite, the anthelmintically active moiety, reached its maximum concentration of 0.322±0.045μgml-1 and 0.384±0.013μgml-1 at 18h and 24h after administration of albendazole alone and co-administration of albendazole with piperonyl butoxide, respectively. Analysis of the data revealed statistically increased albendazole sulphoxide levels at 24 (P 0.05) in values of maximum concentration (normal and calculated) could be observed between groups of goats. However, values of time to reach the concentration maximum (normal and calculated), area under the concentration-time curve (0-∞ and calculated), minimum residence time, distribution half-life, elimination half-life and total area under the first movement of plasma drug concentration-time curve were significantly higher (P < 0.05) in plasma levels of albendazole sulphoxide in goats following single oral co-administration of albendazole with piperonyl butoxide. The faecal egg count reduction and lower 95% confidence limit for the group treated with albendazole alone were 97 and 68%, while for co-administration of albendazole and piperonyl butoxide the values were 99 and 97%, respectively. The ED50 for egg hatch was 0.196, indicating suspected resistance to benzimidazole anthelmintics. The drug combination proved efficacious against an albendazole-resistant nematode parasite population in goats.

The Effect of Fasting on the Plasma Disposition of Albendazole in Goats

This study was designed to investigate the effect of fasting on the plasma disposition of albendazole (ABZ) in goats following oral administration. A total of 10 goats, aged 5-6 months were used in this study. The animals were allocated into two groups (fasted and fed groups) of five animals each. ABZ was administered orally to animals in two groups at 10 mg/kg bodyweight. Heparinize blood samples were collected between 1 h and 144 h after treatment and the plasma samples were analysed by high performance liquid chromatography for ABZ, active albendazole sulphoxide (ABZSO) and inactive albendazole sulphone (ABZSO2) metabolites. ABZ is not detected and ABZSO and ABZSO2 metabolites were present in the samples of fed and fasted animals. Feeding was significantly enhanced the plasma concentration of the ABZSO and ABZSO2 metabolites. The area under the curve (AUC) and half-life (t1/2) of both metabolites were significantly larger and longer in fed compared to fasted animals, respectively. Moreover the maximum plasma concentration (Cmax: 1.06±0.17 µg/ml) of ABZSO2 was also significantly higher in fed group compared with the fasting group (0.72±0.20 µg/ml). The changes in plasma kinetics, reflecting an altered quantitative gastrointestinal absorption or metabolism, were reflected in increased availability of ABZ metabolites in the plasma of fed goats. This could be a strategy to extend the exposure of parasites to the more active metabolite of ABZ and thus to improve the efficacy in goats.

Multiresidue screening method for detection of benzimidazoles and their metabolites in liver and muscle by high-performance liquid chromatography: method development and validation according to Commission Decision 2002/657/EC

The use of veterinary drugs may cause the presence of residues in food of animal origin if appropriate withdrawal periods are not respected. A high-performance liquid chromatography (HPLC) method has been developed for the simultaneous detection of 11 benzimidazole residues, including metabolites – albendazole, albendazole sulphoxide, albendazole sulphone, fenbendazole, fenbendazole sulphoxide (oxfendazole), fenbendazole sulphone, flubendazole, mebendazole, oxibendazole, thiabendazole, 5-hydroxythiabendazole – in bovine, ovine, equine, swine, rabbit and poultry liver and in bovine, swine and fish muscle. After extraction with a dicloromethane/acetonitrile solution (35/65 v/v) containing 5% ammonium hydroxide, the solvent was evaporated to dryness, the residue was dissolved in HCl 0.1 M, defatted with hexane, purified on a strong cation exchange solid-phase extraction cartridge and analysed in HPLC with diode array and fluorescence detectors. The method was validated as screening qualitative method evaluating, according to Commission Decision 2002/657/EC criteria, specificity, CCβ and β error at cut off level of 25 μg/kg and ruggedness.

Development of achiral and chiral 2D HPLC methods for analysis of albendazole metabolites in microsomal fractions using multivariate analysis for the in vitro metabolism

In this work, the development of two multidimensional liquid chromatography methods coupled to a fluorescence detector is described for direct analysis of microsomal fractions obtained from rat livers. The chiral multidimensional method was then applied for the optimization of the in vitro metabolism of albendazole by experimental design. Albendazole was selected as a model drug because of its anthelmintics properties and recent potential for cancer treatment. The development of two fully automated achiral-chiral and chiral-chiral high performance liquid chromatography (HPLC) methods for the determination of albendazole (ABZ) and its metabolites albendazole sulphoxide (ABZ-SO), albendazole sulphone (ABZ-SO2) and albendazole 2-aminosulphone (ABZ-SO2NH2) in microsomal fractions are described. These methods involve the use of a phenyl (RAM-phenyl-BSA) or octyl (RAM-C8-BSA) restricted access media bovine serum albumin column for the sample clean-up, followed by an achiral phenyl column (15.0×0.46cmI.D.) or a chiral amylose tris(3,5-dimethylphenylcarbamate) column (15.0×0.46cmI.D.). The chiral 2D HPLC method was applied to the development of a compromise condition for the in vitro metabolism of ABZ by means of experimental design involving multivariate analysis.

A pharmacology-based comparison of the activity of albendazole and flubendazole against Echinococcus granulosus metacestode in sheep

Cyst echinococcosis (CE) is a zoonotic disease caused by the larval stage of the Echinococcus granulosus helminth parasite. The work reported here aimed to compare the efficacy of albendazole (ABZ) and flubendazole (FLBZ) against CE in naturally infected sheep. Additionally, their comparative pharmacokinetic behaviour and the assessment of serum liver enzymes activities were studied. Twelve (12) naturally infected sheep were allocated to the following experimental groups: unmedicated control group, FLBZ-treated and ABZ-treated.Treatments were orally performed every 48h, over 55 days at dose rate of 10 (FLBZ) and 8.5 (ABZ)mg/kg (equimolar dose rates). The efficacy of the drug treatments was based on protoscoleces’ vitality/viability. The kinetic disposition assessment included the Initial and Final Kinetic Studies which implicated the collection of blood samples after both the first and the last drug administration. Blood samples were processed to measure drug concentrations by HPLC. The protoscoleces’ vitality observed in the untreated control group (98%) was significantly reduced in the presence of both ABZ and FLBZ. 90% of mice inoculated with protoscoleces in the control group developed hydatid cysts in their peritoneal cavity (viability study). However, only 25% (FLBZ) and 33% (ABZ) of mice inoculated with protoscoleces recovered from treated sheep, developed hydatid cysts in their abdominal cavity. Reduced FLBZ (R-FLBZ) was the main metabolite recovered in the bloodstream after oral administration of FLBZ to sheep. Low plasma concentrations of FLBZ parent drug were measured up to 48h post-administration. ABZ was not detected in plasma at any time post-treatment, being its metabolites ABZ sulphoxide (ABZSO) and ABZ sulphone (ABZSO2) recovered in plasma. Hepatotoxicity due to the continued treatment with either ABZ or FLBZ was not observed. A 3-fold increase ethoxyresorufin O-deethylase activity, a cytochrome P450 1A (CYP1A)-dependent enzyme reaction, was observed in liver microsomes obtained from sheep receiving ABZ, compared to those of the unmedicated and FLBZ-treated animals. In conclusion, FLBZ is an available anthelmintic which may be developed into an effective and safe drug for the human CE treatment. Despite the low plasma concentrations measured by FLBZ/R-FLBZ, an important reduction in protoscoleces’ vitality was observed in cysts located in sheep liver. Modern pharmaceutical technology may help to greatly improve FLBZ systemic exposure improving its efficacy against CE.

Anthelmintics residues in raw milk. Assessing intake by a children population

Anthelmintics, such as benzimidazoles and probenzimidazoles, are veterinary drugs used against endoparasites in food producing animals. A number of these drugs are considered responsible for embryotoxicity and teratogenicity. The residue levels of Albendazole, Febantel, Fenbendazole, Mebendazole and some of their metabolites (Albendazole sulphoxide, Albendazole sulphone, Fenbendazole sulfone) were assessed in 123 (42 goat, 69 sheep, 12 bovine) raw milk samples collected from all farms throughout Southern Greece. Sample analysis was performed by HPLC with Diode Array Detector. A high percentage (27.6%) of the samples examined was found to be positive for the investigated compounds. In 14 samples (11.4%), the residues' concentration exceeded the established Maximum Residue Limits. Estimated Daily Intakes were calculated for a population of 723 children aged 10-12 years. Data on milk consumption were obtained by personal interview through a 7-day food frequency questionnaire. The maximum Estimated Daily Intakes for the anthelmintic residues, concerning raw milk, did not exceed the current Acceptable Daily Intake.

Development of an Evidence biochip array kit for the multiplex screening of more than 20 anthelmintic drugs

Anthelmintic drugs are used in clinical and veterinary practice for the treatment of infections caused by parasitic worms. Their extensive use in food-producing animals can cause the presence of residues in food. For consumer protection it is necessary to monitor the levels of anthelmintic residues to ensure that they remain within the legally permitted maximum acceptable concentrations. For this purpose, the use of multiplex screening methods is advantageous. Biochip array technology allows the simultaneous determination of multiple analytes from a single sample at a single point in time. This study reports the development of an Evidence biochip array for the multiplex screening of anthelmintic drugs. Simultaneous competitive chemiluminescent immunoassays are employed. The solid support and vessel is the biochip, which contains an array of discrete test sites. The assays were applied to the semiautomated bench-top analyser Evidence Investigator. The aminobenzimidazoles assay detected aminomebendazole, albendazole 2-aminosulphone and aminoflubendazole, the avermectins assay detected emamectin benzoate, eprinomectin, abamectin, ivermectin and doramectin, the benzimidazoles assay detected albendazole sulphone, albendazole, albendazole sulphoxide, oxibendazole, oxfendazole and flubendazole, the thiabendazole assay detected cambendazole, thiabendazole and 5-hydroxythiabendazole and the triclabendazole assay detected ketotriclabendazole, triclabendazole and triclabendazole sulphoxide. The limits of detection ranged from 0.3 ppb (aminobenzimidazoles) to 2.0 ppb (levamisole) in milk and from 0.15 ppb (aminobenzimidazoles) to 6.5 ppb (levamisole) in tissue. The average recovery range was 71-135 %. This multianalytical approach on a biochip platform is applicable to the screening of more than 20 anthelmintic drugs in different food matrices, leading to consolidation of tests and enhancement of the test result output.

Multiresidue HPLC method to measure benzimidazole anthelmintics in plasma and egg from laying hens. Evaluation of albendazole metabolites residue profiles

A method to quantify residual concentrations of benzimidazole (BZD) anthelmintic drugs in plasma and total egg from laying hens was developed and validated. The analytical method allowed detection of ten (10) BZD molecules by HPLC with UV detection: albendazole (ABZ) and its metabolites, albendazole sulphoxide (ABZSO), albendazole sulphone (ABZSO2) and amino albendazole sulphone (NH2-ABZSO2); fenbendazole (FBZ) and its metabolites, fenbendazole sulphoxide (FBZSO) and fenbendazole sulphone (FBZSO2); and flubendazole (FLBZ) and its reduced (FLBZ-R) and hydrolysed (FLBZ-H) metabolites. Analytes were separated on a C18 reversed-phase column using a mobile phase compose of acetonitrile and ammonium acetate buffer (0.025M, pH 5) at a flow rate of 1.2mLmin−1. The total run time for the method was 25min. The egg and plasma extraction processes were based on liquid–liquid extraction obtaining recoveries between 68.9% and 98.3% (egg) and from 71.4% to 100% (plasma). The linearity of the method was demonstrated with correlation coefficients ranging between 0.995 and 0.999 (egg) and between 0.993 and 0.997 (plasma). The method exhibited a high degree of intra- and inter-day precision and accuracy demonstrated by the low CV (⩽14.1% for egg, and ⩽7.79% for plasma) and relative error (RE) (from 0.628% to 8.30% for egg and between 2.89% and 9.08% for plasma). The LOQ were low and accurate enough for the application of the method to study the plasma pharmacokinetic disposition of ABZ metabolites and their residual concentrations in eggs following an oral administration of ABZ to laying hens. ABZ parent drug and its ABZSO and ABZSO2 metabolites were measured in plasma. The ABZSO and ABZSO2 plasma concentrations were much higher than that of the parent drug, with Cmax values of 2.22 and 1.50μg/mL, respectively. The AUC values were 21.02 and 23.08μgh/mL for ABZSO and ABZSO2. Residual ABZSO and ABZSO2 concentrations were also measured in eggs. The assessment of the plasma disposition kinetics and egg residues after ABZ administration to laying hens is presented as an application of the developed analytical methodology.

Albendazole and its metabolites in the breast milk of lactating women following a single oral dose of albendazole.

Albendazole (ABZ) is used in several anthelminthic drug programs. ABZ side-effects are generally mild, but ABZ-induced pancytopenia may be serious. In filariasis programmes, it may be necessary to administer ABZ to breastfeeding women. Few data are available on safety of ABZ for breastfed infants. In addition, the pharmacokinetics of ABZ and its metabolites in human milk is insufficiently investigated. The aim was to study pharmacokinetics of ABZ and its metabolites [ABZ sulphoxide (ABSX) and ABZ sulphone] in the breast milk lactating women after one single oral dose of ABZ. Thirty-three lactating women (age 18-40 years) participated in the study. They received a single oral 400-mg dose of ABZ. Five milk samples were taken at 0, 6, 12, 24 and 36 h. One serum sample was taken after 6 h. Samples were analysed using high-performance liquid chromatography and pharmacokinetic analysis was performed. ABZ was detectable in milk samples 6 h after the oral dose. The mean concentration of serum ABZ was 63.7 +/- 11.9 ng ml(-1). The pharmacokinetic parameters for ABSX were calculated as follows: 351.9 +/- 32.4 ng ml(-1), 6.9 +/- 0.5 h, 12.4 +/- 2.2 h and 5190.3 +/- 482.8 ng*h ml(-1) for C(max), T(max), t((1/2)) and AUC(0-36), respectively. The milk-to-serum ratios (range) for ABZ and ABSX were 0.9 (0.2-6.5) and 0.6 (0.1-1.5), respectively. After an oral dose of 400 mg, ABZ and ABSX attain low concentrations in breast milk that are unlikely to be considered harmful for the breastfed infant.

Pharmacological assessment of netobimin as a potential anthelmintic for use in horses: Plasma disposition, faecal excretion and efficacy

This study aimed to determine the plasma disposition and faecal excretion of netobimin (NTB) and its respective metabolites as well as the efficacy against strongyles in horses following oral administration. Netobimin (10 mg/kg) was administered orally to 8 horses. Blood and faecal samples were collected from 1 to 120 h post-treatment and analysed by high performance liquid chromatography (HPLC). Using a chiral phase-based HPLC, plasma disposition of ABZSO enantiomers produced was also determined. Faecal strongyle egg counts (EPG) were performed by a modified McMaster’s technique before and after the treatment. Neither NTB nor ABZ were present and only albendazole sulphoxide (ABZSO) and sulphone metabolites (ABZSO 2) were detected in the plasma samples. Maximum plasma concentration of ABZSO (0.53 ± 0.14 μg/ml) and ABZSO 2 (0.36 ± 0.09 μg/ml) were observed at ( t max) 10.50 and 19.50 h, respectively following administration of NTB. The area under the curve (AUC) of the two metabolites was similar to each other. Netobimin was not detected, and ABZ was predominant in faecal samples. The maximum plasma concentration ( C max) of (−)ABZSO was significantly higher than (+)ABZSO, but the area under the curves (AUCs) of the enantiomer were not significantly different each other in plasma samples. The enantiomers of ABZSO were close to racemate in the faecal samples analyzed. Netobimin reduced the EPG by 100%, 100%, 77%, 80% and 75% 2, 4, 6, 8 and 10 weeks post-treatment, respectively. The specific behaviour of the two enantiomers probably reflects different enantioselectivity of the enzymatic systems of the liver which are responsible for sulphoxidation and sulphonation of ABZ. Considering the pharmacokinetic and efficacy parameters NTB could be used as an anthelmintic in horses.

Determination of albendazole metabolites by direct injection of bovine plasma and multidimensional achiral–chiral high performance liquid chromatography

The development and validation of a fully automated achiral–chiral high performance liquid chromatography (HPLC) method for the simultaneous determination of albendazole metabolites: enantiomers of albendazole sulphoxide (ABZ-SO), albendazole sulphone (ABZ-SO 2) and albendazole 2-aminosulphone (ABZ-SO 2NH 2) in bovine plasma are described. This method involves an octyl restricted access media bovine serum albumin column (C 8-RAM-BSA) (50 mm × 4.6 mm I.D.) for sample clean-up, followed by enantioselective analysis on a column containing an amylose tris(3,5-dimethylphenylcarbamate) stationary phase (150 mm × 4.6 mm I.D.). The chromatographic separations of all target compounds were performed at 30 °C using a mobile phase composed of phosphate buffer (10 mmol L −1; pH 7.5):acetonitrile (60:40, v/v), flow rate of 0.5 mL min −1 and fluorescence detection at 290 nm and 320 nm, excitation and emission, respectively. The influence of different organic modifiers and chiral selector of the stationary phase on enantioseparation of ABZ-SO was investigated. The method developed was fully validated. The calibration curves were linear in the concentration range of 40.00–1280 ng mL −1 for each albendazole sulphoxide enantiomer, 10.0–320 ng mL −1 for albendazole sulphone and 20.0–320 ng mL −1 for albendazole 2-aminosulphone. The inter- and intra-day precision ranged from 0.760% to 7.79% relative standard deviation (R.S.D.), and the accuracy ranged 101% from 114% of the nominal values while the transfer efficiency was in the range of 84.4–103%. The method showed good linearity, precision, accuracy, sensitivity and selectivity allowing it to be appropriate for further pharmacokinetics and metabolism studies of albendazole.

Plasma Disposition and Faecal Excretion of Netobimin Metabolites and Enantiospecific Disposition of Albendazole Sulphoxide Produced in Ewes

Netobimin (NTB) was administered orally to ewes at 20 mg/kg bodyweight. Blood and faecal samples were collected from 1 to 120 h post-treatment and analysed by high-performance liquid chromatography (HPLC). Using a chiral phase-based HPLC, plasma disposition of albendazole sulphoxide (ABZSO) enantiomers produced was also determined. Neither NTB nor albendazole (ABZ) was present and only ABZSO and albendazole sulphone (ABZSO(2)) metabolites were detected in the plasma samples. Maximum plasma concentrations (C(max)) of ABZSO (4.1 +/- 0.7 microg/ml) and ABZSO(2) (1.1 +/- 0.4 microg/ml) were detected at (t(max)) 14.7 and 23.8 h, respectively following oral administration of netobimin. The area under the curve (AUC) of ABZSO (103.8 +/- 22.8 (microg h)/ml) was significantly higher than that ABZSO(2)(26.3 +/- 10.1 (microg h)/ml) (p < 0.01). (-)-ABZSO and (+)-ABZSO enantiomers were never in racemate proportions in plasma. The AUC of (+)-ABZSO (87.8 +/- 20.3 (microg h)/ml) was almost 6 times larger than that of (-)-ABZSO (15.5 +/- 5.1 (microg h)/ml) (p < 0.001). Netobimin was not detected, and ABZ was predominant and its AUC was significantly higher than that of ABZSO and ABZSO(2), following NTB administration in faecal samples (p > 0.01). Unlike in the plasma samples, the proportions of the enantiomers of ABZSO were close to racemic and the ratio of the faecal AUC of (-)-ABZSO (172.22 +/- 57.6 (microg h)/g) and (+)-ABZSO (187.19 +/- 63.4 (microg h)/g) was 0.92. It is concluded that NTB is completely converted to ABZ by the gastrointestinal flora and absorbed ABZ is completely metabolized to its sulphoxide and sulphone metabolites by first-pass effects. The specific behaviour of the two enantiomers probably reflects different enantioselectivity of the enzymatic systems of the liver that are responsible for sulphoxidation and sulphonation of ABZ.

Pharmacokinetics of Ricobendazole After its Intravenous, Intraruminal and Subcutaneous Administration in Sheep

Ricobendazole (RBZ) was administered in sheep at the dose rate of 5 mg/kg by intravenous (i.v.) route as a 10% experimental solution, by the intraruminal (i.r.) route as a 10% experimental suspension, and by the subcutaneous (s.c.) route as a 10% commercial formulation available in Argentina. Blood samples were drawn during a 60 h period. Plasma concentrations of RBZ and its inactive metabolite albendazole sulphone (ABZSO2) were determined by high-performance liquid chromatography. The pharmacokinetic parameters were determined by compartmental analysis. The fitting of the data was done by weighted least-squares non-linear regression analysis. The pharmacokinetic parameters were estimated for every animal by simultaneous fitting of the plasma concentrations profiles of RBZ obtained after its administration by the three routes. The kinetic analysis of ABZSO2 was performed by a statistical moment approach. Ricobendazole bioavailability was poor after i.r. administration, whereas high and sustained plasma concentrations and higher bioavailability were obtained after s.c. administration. A simple two-compartment open model explains in a mechanical sense the pharmacokinetic behaviour of RBZ in sheep and allows us to estimate the real first-order constant rate of absorption and the loss of drug from the absorption site after its administration by s.c. and i.r. routes.