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Albendazole versus ricobendazole (albendazole-sulphoxide) against enteral and parenteral stages of Trichinella spiralis in mice.

Comparison of the anthelmintic activity and pharmacokinetic profiles following albendazole (ABZ) and albendazole-sulphoxide (ricobendazole = RBZ) administration was made in a mouse model for helminthic infections. Swiss CD-1 mice were experimentally infected with Trichinella spiralis and treated with either ABZ or RBZ at 3 different stages of the parasite life-cycle: pre-adult (day 1 p.i.), migrating larvae (days 13, 14 and 15 p.i.) and encysted muscle larvae (days 34, 35 and 36 p.i.). Plasma concentrations of albendazole-sulphoxide (ABZSO) were measured in age matched non-infected mice by high performance liquid chromatography (HPLC), after administration of ABZ or RBZ dosed at 50 mg ABZ equivalent kg-1. ABZSO pharmacokinetic profiles following ABZ or RBZ administration were similar, although the Tmax (1.83 +/- 0.30 and 0.41 +/- 0.28, respectively) were significantly different (P < 0.01). Against pre-adult stages ABZ was significantly (P < 0.05) more effective than RBZ when administered at 10 mg kg-1 (96.5% and 78.0% reduction with respect to the control group). Migrating and encysted larvae were less sensitive to both compounds and dose rates had to be increased to 100 mg kg-1 to achieve significant efficacies. Against parenteral stages, ABZ was significantly more effective than RBZ when both were given at 100 mg kg-1 (64.0% and 44.2% reduction against migrating larvae and 94.7% and 65.5% reduction against encysted larvae, respectively). In conclusion, RBZ was not more effective than ABZ against enteral and parenteral stages of Trichinella spiralis.

Albendazole↗

Improving bioavailability and anthelmintic activity of albendazole by preparing albendazole-cyclodextrin complexes.

The bioavailability and anthelmintic activity of albendazole-cyclodextrin complexes (ABZ-CDC) compared to albendazole suspensions in carboxymethylcellulose (ABZ-CMC) was assessed in a mouse model for Trichinella infections. Swiss CD-1 mice experimentally infected with T. spiralis were treated with both formulations against enteral (adult worms) and parenteral (migrating and encysted larvae). Oral bioavailability was assessed in age matched mice treated with 50 mg/kg of both formulations. The anthelmintic effects and plasma concentration of the active metabolite albendazole-sulphoxide (ABZSO) enantiomer (-) were significantly increased following administration of ABZ-CDC in relation to ABZ-CMC.

2-Hydroxypropyl-beta-cyclodextrin↗

Metabolism of albendazole and albendazole sulphoxide by ruminal and intestinal fluids of sheep and cattle.

1. The metabolism of albendazole (ABZ), albendazole sulphoxide (ABZSO) and albendazole sulphone (ABZSO2) by ruminal, abomasal and ileal fluids of sheep and cattle was investigated under anaerobic conditions in vitro. 2. None of the compounds was metabolically changed by incubation with abomasal fluids of sheep and cattle. 3. ABZ and ABZSO were extensively metabolized by sheep and cattle ruminal and ileal fluids. ABZSO2 was unaffected by incubation with these gastrointestinal fluids. 4. The rate of ABZ oxidation into ABZSO was greater for cattle ruminal and ileal fluids than for sheep fluids. 5. ABZSO was reduced back to ABZ by ruminal and ileal fluids of both species. This reducing activity was significantly higher for both ruminal and ileal fluids of sheep compared with those of cattle.

Abomasum↗

Overberg research projects. XIII. A comparison of the efficacy of albendazole drench and an albendazole slow-release capsule against nematode parasites in sheep.

The anthelmintic efficacy of albendazole intra-ruminal slow-release capsules (SRC) and albendazole drench against field strains of 5 genera of nematode parasites of sheep, where compared. The SRC reduced the number of L4 and adult Nematodirus by 64.1% and 58.3% and the albendazole drench by 98.1% and 99.1%, respectively. Neither formulation was more than 89.5% effective against either the L4 or adult stage of Teladorsagia. The efficacy of both formulations against the adult stages of Haemonchus, Trichostrongylus and Oesophagostomum ranged from 95.9 to 99.9%.

Albendazole↗

[Uptake and release of mebendazole, albendazole and albendazole sulfoxide by secondary cysts of Echinococcus granulosus in vitro].

Mebendazole (Meb), albendazole (Alb) or albendazole sulfoxide (AlbSO) were taken rapidly in vitro by secondary cysts of Echinococcus granulosus removed out from mice infected with protoscoleces 8-9 months previously. The amounts of the drugs taken by the cysts were apparently increased followed by exposure of the cysts to the drugs at 10 micrograms.ml-1. The Alb penetrated into the cysts was distributed mainly in cyst wall, whereas the content of Meb in cyst wall was twice as much as that in cyst fluid. The distributions of AlbSO in cyst wall and cyst fluid were similar. When the cysts in the medium were exposed to Alb, some AlbSO and albendazole sulphone were detected in both cyst wall and cyst fluid, indicating that a part of Alb was metabolized by the cysts. In another experiment cysts exposed to the drug for 2 h were transferred to the medium without the drug for another 24 h. The release rates of the 3 drugs from the cysts were alike. In 1-2 h after transfer about 65-70% of the drugs absorbed by the cysts previously were released. Twenty-four hours after exposure the release rates increased to 75-85%, and the release of the drugs from the cyst wall was somewhat faster than that from cyst fluid.

Albendazole↗

Therapeutic monitoring of albendazole: a high-performance liquid chromatography method for determination of its active metabolite albendazole sulfoxide.

A sensitive and specific reversed-phase high-performance liquid chromatography (HPLC) method is described for the quantitative determination of albendazole sulfoxide (ASOX); since albendazole sulfone (ASON) appears only in small amounts and albendazole (ABZ) normally does not appear in human plasma, only a qualitative determination of ASON and ABZ was made in human plasma. Plasma samples were extracted three times using ethylacetate and petroleum benzine; this yielded optically clear samples which after evaporation were dissolved in the HPLC solvent and injected onto an RP-C18 column, with ultraviolet detection at 290 nm. The detection limit of the main metabolite ASOX was 50 nM and that of ASON was 100 nM. The intraday coefficient of variation for ASOX was 3.3% at a concentration of 2.2 microM, and the interday coefficients of variation were 14.5, 7.3, and 9.1% at ASOX concentrations of 0.5, 2.5, and 5.0 microM, respectively. Calibration was linear in a concentration range of 0.05-12 microM for ASOX and 0.1-8 microM for ASON, respectively. Pharmacokinetic data of a patient with echinococcosis are presented.

Albendazole↗

The effects of albendazole and albendazole sulphoxide combination-therapy on Echinococcus granulosus in vitro.

Protoscoleces of Echinococcus granulosus were incubated in vitro with decreasing concentrations of either albendazole (ABZ) or albendazole sulphoxide (ABZ.SO) (50, 10, 1 and 0.1 micrograms ml-1), and in combination. Viability was assessed by the methylene blue exclusion test and establishment of infection in mice. Protoscolex ultrastructure was determined by means of transmission and scanning electron microscopy. ABZ and ABZ.SO, when used separately had protoscolicidal activity after a longer incubation period (30 days) than when used as combined compounds. When incubated in the presence of ABZ + ABZ.SO, protoscolex viability dropped rapidly. That is, protoscoleces were all non-viable at 12 days of exposure, with no cyst developing following their inoculation into mice. The ultrastructural changes induced by ABZ or ABZ.SO alone, were: (a) rostellar disorganization, (b) formation of numerous blebs on the tegument, (c) loss of the microtriches, (d) increased vesiculation within the tegumentary cytons together, (e) an increase in lipid deposits and (f) depletion of glycogen reserves. After incubation with combined ABZ and ABZ.SO the tegument contained numerous blebs which became detached, leaving debris only, some intact nuclei being discernible in the protoscolex parenchyma.

Albendazole↗

Effects of albendazole and albendazole sulfoxide on cultures of differentiating rodent embryonic cells.

Micromass cell culture systems for rat embryo midbrain (CNS) and limb bud (LB) cells were employed to assess the in vitro developmental toxicity of the human and veterinary anthelmintic albendazole (ABZ) and its sulfoxide metabolite (SOABZ). ABZ is reported to be teratogenic in rats, and is extensively metabolized to the sulfoxide derivative. It has been postulated that SOABZ is the reactive metabolite responsible for albendazole's developmental toxicity and anthelmintic activity in vivo. Three parameters for assessing developmental toxicity were measured: cell growth, differentiation, and cytotoxicity. CNS and LB cultures were equivalent in their sensitivities to both ABZ and SOABZ. ABZ was approximately 50-fold more potent than SOABZ. Immunohistochemical determinations of tubulin organization revealed that both ABZ and its sulfoxide metabolite elicit an accumulation of cells in the mitotic phase of the cell cycle. Since ABZ is one of the most potent agents tested in the micromass system to date, this anthelmintic should be considered a potential developmental toxicant.

Albendazole↗

Rapid and sensitive method for the determination of albendazole and albendazole sulphoxide in biological fluids.

A sensitive and selective reversed-phase high-performance liquid chromatographic method for the determination of albendazole and its active metabolite albendazole sulphoxide in plasma has been developed. It involves single-step extraction of plasma with dichloromethane, evaporation of the solvent and chromatography on a muBondapak phenyl column with a mobile phase of water containing 1% (v/v) triethylamine-methanol-acetonitrile (70:10:20, v/v) at pH 3.1. Run time is 12 min. The assay satisfies all of the criteria required for use in clinical pharmacokinetic studies and possesses important advantages, notably speed and expense, over current methods.

Adult↗

Simultaneous determination of albendazole sulfoxide enantiomers and albendazole sulfone in plasma.

A high-performance liquid chromatographic method has been developed for the simultaneous determination of albendazole sulfoxide (ABZSO) enantiomers and albendazole sulfone (ABZSO2) in human plasma. The resolution of ABZSO enantiomers and ABZSO2 was obtained on a Chiralpak AD column using hexane-isopropanol-ethanol (81:14.25:4.75, v/v/v) as the mobile phase. The drugs were detected by fluorescence (lambda(exc) = 280 nm, lambda(em) = 320 nm). The drugs were extracted from 500 microl plasma with ethyl acetate, and after solvent evaporation, the residues were dissolved in the mobile phase and chromatographed. The method was precise and accurate for the three compounds, as judged by the coefficients of variation and relative errors observed. Linear standard curves were obtained in the concentration range of 5-2500 ng/ml for ABZSO enantiomers and 1-500 ng/ml for ABZSO2. A typical plasma concentration-time profile is presented for one patient under treatment for neurocysticercosis.

Albendazole↗

[Effect of mebendazole, albendazole and albendazole sulfoxide on glycogen contents of Echinococcus granulosus cysts in infected mice].

Mice infected with protoscoleces of Echinococcus granulosus for 8-9 months were treated ig with mebendazole (Meb) 50 mg.kg-1.d-1, albendazole (Alb) 300 mg.kg-1.d-1 or albendazole sulfoxide (AlbSO) 150 mg.kg-1.d-1 for 1-7 d. The glycogen contents of cyst wall in each drug groups were 1.0 +/- 0.6 - 1.8 +/- 0.9 mg/g, 1.1 +/- 0.9 - 1.8 +/- 0.8 mg/g and 0.8 +/- 0.5 - 1.5 +/- 0.9 mg/g, respectively, which were less than those 2.2 +/- 1.3 - 2.8 +/- 1.3 mg/g of corresponding control groups with respective glycogen reduction rates of 38-55%, 36-51% and 46-62%. After prolongation of treatment course to 10-14 d, the glycogen contents of cyst wall in Meb and AlbSO groups were further decreased, which resulted in glycogen reduction rates of 73% and 69%, respectively. No further decrease of glycogen contents in Alb groups was seen as the glycogen reduction rates sustained in 32%. Histochemical observation showed that the glycogen contents in germinal layer of the cysts decreased significantly or even disappeared during the treatment of Meb, Alb or AlbSO. The results suggested that the effects of Meb and AlbSO on mice infected with secondary cysts of E granulosus were superior to Alb as evaluated by glycogen reduction rate of cyst wall.

Albendazole↗

Bioavailability comparison between albendazole and albendazole sulphoxide in rats and man.

Albendazole (ABZ) is a broad spectrum anthelmintic benzimidazole with very low bioavailability, and its activity is due to its main metabolite, Albendazole sulphoxide (ABZS). This work demonstrates the improvement of bioavailability when the ABZS is directly administered, compared with the ABZ administration, both orally given. This observation may be used as an interesting target in the design of new drugs with antihelmintic activity in systemic diseases, using ABZS as a parent drug.

Adult↗

Comparative metabolism of albendazole and albendazole sulphoxide by different helminth parasites.

Albendazole (ABZ) is a broad-spectrum benzimidazole anthelmintic widely used in human and veterinary medicine. The aim of the current work was to characterise the sulphoxidative metabolism of ABZ, and the sulphoreduction of ABZ sulphoxide (ABZSO), by microsomal (Ms) and cytosolic (Cyt) fractions of three different helminth species: Fasciola hepatica, Moniezia expansa and Ascaris suum. After the incubation assays, parasite material was analysed by HPLC to characterise the metabolic product formed. Both the Ms and Cyt fractions of the three parasites studied were able to oxidise ABZ into ABZSO in a non-enantioselective fashion. Oxidation of ABZ was greater in the Ms fraction of the trematode (50%) than in both cestode (19%) and nematode (14%) parasites. Only the incubation of ABZSO with both subcellular fractions of M. expansa generated ABZ as a metabolic product. The results obtained here indicate that helminths have the capacity to biotransform benzimidazole compounds; however, this metabolic activity differs qualitatively and quantitatively among helminth species.

Albendazole↗

Albendazole repeated administration induces cytochromes P4501A and accelerates albendazole deactivation in mouflon (Ovis musimon).

Adult mouflon ewes (Ovis musimon) were treated repeatedly with therapeutic doses of albendazole (ABZ, p.o. 7.5 mg/kg of body weight/day, for five consecutive days). Animals (treated or control) were sacrificed 24 h after the fifth dose of ABZ and liver and small intestine were collected to prepare microsomes. The activities of several biotransformation enzymes were measured in both hepatic and intestinal microsomes. A significant increase in the activity and amount of cytochromes P4501A (CYP1A) was observed in both tissues of ABZ treated mouflons compared to control animals. No other biotransformation enzymes tested were affected by five ABZ doses. The in vitro biotransformation of ABZ was studied in hepatic and intestinal microsomes from ABZ treated and control mouflons. Concentrations of two main ABZ metabolites - pharmacologically active ABZ sulfoxide and pharmacologically inactive ABZ sulfone were analysed using HPLC. A significant increase in rate of formation of ABZ sulfone (which is catalysed by CYP1A) was observed in hepatic as well as in intestinal microsomes from ABZ treated animals. The enhancement of ABZ deactivation by its repeated administration may affect the anthelmintic efficacy of this drug and may contribute to the development of parasite resistance.

Albendazole↗

Uptake of albendazole and albendazole sulphoxide by Haemonchus contortus and Fasciola hepatica in sheep.

The pattern of in vivo uptake of albendazole (ABZ) and its major metabolite, ABZ-sulphoxide (ABZSO), by Haemonchus contortus and Fasciola hepatica recovered from ABZ-treated sheep, was investigated. Concentration profiles of both compounds were simultaneously measured in target tissues/fluids from the same infected sheep. In addition, the proportion of the (+) and (-) ABZSO enantiomers was determined in plasma, bile and F. hepatica recovered from treated sheep. Sheep naturally infected with H. contortus were intraruminally (i.r.) treated with ABZ (micronized suspension, 7. 5mg/kg) and the plasma concentrations of ABZSO and ABZ-sulphone (ABZSO(2)) determined in addition to the concentration of ABZ and ABZSO in H. contortus, abomasal mucosa and fluid content samples. In addition, F. hepatica artificially infected sheep were treated i.r. with the same ABZ suspension (7.5mg/kg), and samples of blood, bile, liver tissue and adult flukes were collected and analysed by HPLC to determine the concentrations of ABZ and both enantiomers of ABZSO. ABZSO and ABZSO(2) were the analytes recovered in plasma with ABZ and ABZSO present in H. contortus. ABZ was the analyte recovered at the highest concentration in H. contortus and abomasal mucosa, whereas higher concentrations of ABZSO were measured in abomasal fluid content. Only low concentrations of ABZ were detected in F. hepatica and bile, but markedly higher concentrations of ABZ were measured in liver tissue. ABZSO was the main molecule recovered in F. hepatica, plasma and bile samples collected from ABZ-treated sheep. The (+) enantiomer of ABZSO was recovered at a higher proportion in plasma (75%), bile (78%) and F. hepatica (74%) after ABZ administration to infected sheep.

Abomasum↗

Population genetics of concurrent selection with albendazole and ivermectin or diethylcarbamazine on the possible spread of albendazole resistance in Wuchereria bancrofti.

The Global Program for the Elimination of Lymphatic Filariasis (GPELF) intends to achieve its aims through yearly mass treatments with albendazole (ABZ) combined with ivermectin (IVM) or diethylcarbamazine (DEC). The use of ABZ and IVM separately to combat parasites of veterinary importance has, on many occasions, resulted in widespread drug resistance. In order to help predict the spread of potential ABZ resistance alleles through a population of Wuchereria bancrofti, we have developed a mathematical model that incorporates population genetics into EPIFIL, a model which examines the transmission dynamics of the parasite. Our model considers the effect of the combined treatments on the frequency of a recessive allele, which confers ABZ resistance. The model predicts that after 10 yearly treatments with ALB and DEC, 85% coverage and an initial resistance allele frequency of 5%, the frequency of the resistance genotype will increase from 0.25 to 12.7%. If non-random mating is assumed, the initial genotype frequency will be 2.34% and will increase to 62.7%. ABZ and IVM combination treatment may lead to weaker selection for this genotype. Treatment coverage, initial allele frequencies and number of treatments also affect the rate of selection.

Albendazole↗

Enhanced plasma and target tissue availabilities of albendazole and albendazole sulphoxide in fasted calves: evaluation of different fasting intervals.

The influence of different pre- and post-treatment fasting periods on the plasma availability and disposition kinetics of albendazole (ABZ) and its sulphoxide metabolite (ABZSO) in cattle was investigated. The effect of fasting on the distribution of ABZ and ABZSO to different target tissues/fluids was also characterised. In Experiment I, 35 parasite-free Holstein calves were divided into seven groups according to the following feeding conditions and treated intraruminally with ABZ (10 mg/kg): control group (fed ad libitum), 24 h fasting either prior to (24 h pre-) or post (24 h post-) treatment, 24 h fasting with either 6 (6 h pre + 18 h post) or 12 h (12 h pre + 12 h post-) of feed restriction prior to treatment, 12 h fasting either prior to (12 h pre-) or post (12 h post) treatment. In Experiment II, calves from the same pool of animals were subjected to a 24 h fasting period prior to the same ABZ treatment and killed (two animals) at either 24, 36 or 48 h post-administration to obtain samples of abomasal/intestinal mucosa and fluid contents, bile and lungs. Plasma (Experiment I) and tissues/fluids (Experiment II) samples were analysed by HPLC. All the fasting periods investigated induced marked changes to the plasma availability and disposition kinetics of the ABZSO metabolite. Enhanced plasma availability between 37 and 118%, delayed peak concentrations and extended mean residence times for ABZSO were observed in fasted compared to fed calves. The changes in plasma kinetics, reflecting an altered quantitative gastrointestinal absorption, were reflected in increased availability of ABZ and ABZSO in the target tissues/fluids of fasted calves. The availabilities of ABZ and ABZSO in the gastrointestinal mucosa and fluids in fasted calves were markedly greater than in those fed ad libitum.

Albendazole↗

Presystemic metabolism of albendazole: experimental evidence of an efflux process of albendazole sulfoxide to intestinal lumen.

Albendazole (ABZ) presystemic clearance was studied in rat by perfusion of a 25 microM ABZ solution in isolated intestinal loops. Significant secretion of the active metabolite, ABZSO, into the lumen was observed. The metabolite was also present in mesenteric blood. After 30 min of intestinal perfusion, 64% of the ABZ dose had disappeared from lumen. The total amount of ABZSO measured was 0.341 +/- 0.04 nmol/cm with 0.176 +/- 0.03 nmol/cm in mesenteric blood. The metabolite secretion to intestinal lumen was 0.165 +/- 0.05 nmol/cm. Intestinal sulfoxidation was induced by repeated administration of ABZ and ABZ coadministered with surfactants, especially polysorbate 80. The enantioselectivity of the in vitro intestinal sulfoxidation of ABZ showed that the relative contribution of P-450 and flavin-containing monooxygenase was quite similar, but after the induction by ABZ coadministered with polysorbate 80, the cytochrome P-450 system contribution was significantly increased. The appearance of ABZSO in mesenteric blood clearance was also increased under these conditions.

Albendazole↗