Phase I biotransformation of albendazole in lancet fluke (Dicrocoelium dendriticum)

Dicroceliosis, a lancet fluke infection, is a frequent parasitosis of small ruminants and the anthelmintic drug albendazole (ABZ) is effective in control of this parasitosis. The aim of our project was to study the metabolism of ABZ and ABZ sulphoxide (ABZ.SO) in lancet fluke. Both invitro (subcellular fractions of fluke homogenates) and exvivo experiments (adult flukes cultivated in medium) were performed for this purpose. ABZ was metabolised invitro by lancet fluke NADPH-dependent enzymes by two oxidative steps (sulphoxidation and sulphonation). The apparent kinetic parameters of these reactions have been determined. In the exvivo experiments, only ABZ sulphoxidation was observed. The stereospecificity in ABZ sulphoxidation invitro was slight, with preferential formation of (+)-ABZ.SO enantiomer. In contrast (−)-ABZ.SO formation predominated in exvivo experiments. Sulphoreduction of ABZ.SO occurred neither invivo nor exvivo. The detection of ABZ oxidative metabolites indicates the presence of drug metabolising oxidases in lancet fluke.     

Interaction of Fasciola hepatica with albendazole and its metabolites

Adult Fasciola hepatica recovered from sheep 12 and 24 h after a single oral dose of albendazole (20 mg/kg) contained significant amounts of two oxidized metabolites of albendazole (ABZ), a sulphoxide (SX) and a sulphone (SO), but not ABZ. Flukes incubated in vitro with 10 microM SX or SO contained these metabolites at a level two to three times the level observed in flukes recovered from sheep 24 h after a curative oral dose of ABZ. The concentration of ABZ in flukes was 10-fold greater than either SX or SO after a 24 h in vitro incubation in 10 microM of the respective drug. Flukes exposed to ABZ in vitro contained two-fold higher SX levels than SX-treated flukes due to a combination of spontaneous oxidation in media and fluke-mediated oxidation of ABZ. Measurement of end-products of glucose metabolism following 24 h incubation in 10 microM of either ABZ, SX or SO did not show a significant difference between treated and untreated flukes.     

Albendazole enantiomeric metabolism and binding to cytosolic proteins in the liver fluke <Emphasis Type="Italic">Fasciola hepatica</Emphasis>

Fascioliasis causes important economic losses in ruminant species all over the world. Its control is largely based on the use of the flukicidal compound triclabendazole (TCBZ). However, its chemically related benzimidazole anthelmintic albendazole (ABZ) is being successfully used to control TCBZ-resistance flukes. This research gains some insights into the comparative molecular behaviour of both anthelmintics within the target fluke. The goals of the current work were: (i) to assess the competitive binding of ABZ and TCBZ to cytosolic proteins of F. hepatica, and (ii) to evaluate the enantioselective biotransformation of ABZ in microsomal fractions obtained from TCBZ-susceptible and TCBZ-resistant strains of the liver fluke. Cytosolic proteins from fluke specimens bound TCBZ with greater affinity (83%) than ABZ (44%) and the fraction of TCBZ bound to cytosolic proteins was not displaced by ABZ. The microsomes from both -susceptible and resistant flukes sulphoxidized ABZ into ABZ sulphoxide (ABZSO). However, this oxidative activity was 49% higher in microsomes from TCBZ-resistant flukes (P < 0.001) with a predominant production of the (+) ABZSO enantiomer. As earlier shown for TCBZ, the results reported here confirm an enhanced ability for ABZ oxidation in TCBZ-resistant flukes. While this enhanced oxidative metabolism of ABZ may cooperate to the resistance phenomenon, other pharmacodynamic-based mechanisms may be involved, which would explain why, although being chemically-related, ABZ remains efficacious against TCBZ resistant flukes under field conditions.     

The effect of albendazole and triclabendazole on colchicine binding in the liver fluke Fasciola hepatica

Albendazole (ABZ) and its sulfoxide (SX) and sulfone (SO) metabolites inhibit the binding of 3H-colchicine, a ligand with high affinity for tubulin to homogenate preparations of the liver fluke Fasciola hepatica. The relative potency of these compounds is SX greater than ABZ greater than SO. The benzimidazoles (cambendazole, parbendazole, oxibendazole and mebendazole), when tested at a concentration of 10 microM, also inhibited colchicine binding to fluke homogenates. However, a potent new benzimidazole flukacide, triclabendazole (TCB), was without effect on colchicine binding to F. hepatica homogenates. When intact flukes were exposed in vitro to 10(-5)M SX for as little as 5 min the subsequent binding of 3H-colchicine to fluke homogenates was significantly reduced. However, flukes recovered from sheep either 12 or 24 h after treatment with ABZ did not have a decreased ability to bind colchicine, although the non-specific binding was higher in flukes from treated sheep, suggesting some interaction of drug with tubulin in vivo. ABZ, SX and SO were effective in preventing embryonation of fluke eggs at doses as low as 0.01 microM, but TCB was without effect at concentrations as high as 10 microM. The results suggest that ABZ exerts at least part of its anthelmintic effect by interaction with fluke tubulin.     

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.     

Mouflon (Ovis musimon) dicrocoeliosis: effects of parasitosis on the activities of biotransformation enzymes and albendazole metabolism in liver

Parasitic infections can modify the host's ability to metabolize drugs and other xenobiotics by altering the biotransformation enzymes; these changes may have various pharmacological, toxicological or physiological consequences. In our study, several activities of liver biotransformation enzymes and in vitro metabolism of albendazole (ABZ) were tested and compared in non-infected mouflons (Ovis musimon) and in mouflons infected by lancet fluke (Dicrocoelium dendriticum). Subcellular fractions of liver homogenates were isolated from 5+5 mouflon rams (1-year-old) parasitologically negative or naturally infected by fluke. From the eight enzyme activities that were assayed, only two activities significantly differ in the case of Dicrocoelium-infected versus non-infected animals. In infected mouflons, a significant increase (53%) of thiobenzamide-S-oxidase (TBSO) activity, corresponding mainly to the activity of flavine monooxygenase (FMO), and significant decrease (60%) of glutathione-S-transferase (GST) activity was observed. In addition, dicrocoeliosis caused the enhancement of ABZ hepatic biotransformation. The velocity of the formation of (+)-ABZ sulfoxide and ABZ sulfone was significantly increased. However, the shifts in ABZ biotransformation were very mild that undesirable alterations in ABZ pharmacokinetic are not expected. From this point of view, the use of ABZ in the therapy of mouflon dicrocoeliosis in young animals can be recommended. The treatment of the same mouflons by other drugs that are mainly conjugated with glutathione, seems to be more problematic; hence, all consequences of documented reduced GST activity should be accounted.     

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.     

Pharmacokinetics in sheep and cattle of albendazole administered by an intraruminal slow release capsule

Forty sheep and 40 heifers were dosed with an intraruminal slow release capsule (IRSRC) constructed to deliver albendazole (ABZ) at a low daily dosage for three months. Blood samples were collected at standardised intervals for 110 days and analysed by high performance liquid chromatography for the quantification of the two main metabolites sulphoxide (SO.ABZ) and sulphone (SO2ABZ). The plasma profiles show sustained concentrations of the active metabolite SO.ABZ for 105 days in sheep (m = 0.06 +/- 0.032 micrograms ml-1) and 85 days in cattle (m = 0.10 +/- 0.019 micrograms ml-1). In both species, the proportions of the metabolites were inverted compared to that observed after a single dosage. The bioavailability of ABZ after the administration of the IRSRC compared with a drench was reduced in sheep but increased in cattle. The IRSRC exhibited a preventive and therapeutic effect for at least three months.     

Assessment of climatic and orographic conditions on the infection by Calicophoron daubneyi and Dicrocoelium dendriticum in grazing beef cattle (NW Spain)

From February 2003 to March 2004, 1148 faecal samples from autochthonous Rubia Gallega cattle breed were collected in 170 farms from Lugo (NW Spain), in order to find out the prevalence and intensity of egg-excretion by Calicophoron daubneyi and Dicrocoelium dendriticum, and the possible influence of external factors as annual mean temperature and rainfall, altitude and mean slope. Twenty-six percent (95% CI 19%, 33%) and the 18% (12, 24) of the farms were infected with rumen and lancet flukes. C. daubneyi egg-output (Me=24) was found in 13% (11, 15) of the individual samples. Six percent (5, 7) of the animals in the study had low D. dendriticum eggs (Me=8). By estimating the odds ratio values it was shown that the highest probability of infection by C. daubneyi was in pastures with a mean slope of less than 13% (OR=1.9) and situated under 600 m (OR=1.6). Annual mean rainfall and temperature were not identified as risk factors for the infection with rumen flukes. Mountainous pastures with a mean slope of higher than 25% (OR=5.8) and situated over 600 m (OR=24.6) where precipitation was high (>1000 mm; OR=7) and temperature low (<11 degrees C; 2.8) had involved the highest risk of infection by D. dendriticum. Because of the prevalences found in this study, employment of suitable management practices with strategic treatments with efficacious anthelmintics are needed to reduce the presence of both trematodes and to increase the health status of grazing beef cattle.     

In vivo and ex vivo uptake of albendazole and its sulphoxide metabolite by cestode parasites: relationship with their kinetic behaviour in sheep

The current experiments correlate the disposition kinetics of albendazole (ABZ) following its intravenous (i.v.) and intraruminal (i.r.) administrations to Moniezia spp.-infected sheep, with the pattern of drug/metabolite uptake by tapeworms collected from treated animals. The ex vivo uptake pattern of ABZ and albendazole sulphoxide (ABZSO) by the same cestode parasite was also investigated. Naturally infected (Moniezia spp.) Corriedale lambs were treated with ABZ by either i.v. (Group A, n = 15) or i.r. (Group B, n = 15) administration at 7.5 mg/kg. Plasma and abomasal fluid samples were obtained over a 120-h period. Two animals per group were killed at 0.5, 1, 2, 4 and 6 h post-treatment; parasite material (tapeworms), bile and intestinal fluid samples were recovered. Furthermore, Moniezia spp. tapeworms obtained from sheep killed at the local abattoir were incubated with either ABZ or ABZSO for different time periods in a Kreb's Ringer Tris buffer (ex vivo experiments). Samples were analysed by high performance liquid chromatography for ABZ, ABZSO and albendazole sulphone (ABZSO2). ABZ plasma concentrations decreased rapidly and were not detectable beyond 10 h following i.v. administration. ABZSO and ABZSO2 were the metabolites recovered in plasma after both treatments. ABZ and its metabolites were extensively distributed to the digestive tract, mainly into the abomasal fluid, after the i.v. and i.r. administrations. The parent drug and its active ABZSO metabolite were recovered in tapeworms collected from both i.v. and i.r. treated lambs. However, the availability of both ABZ and ABZSO was higher in parasite material recovered from i.v. treated animals. The uptake of ABZ by the cestode parasite, both in vivo and ex vivo, was significantly greater than that of its sulphoxide metabolite, which agrees with the higher lipophilicity of the parent drug.     

Distribution and characterization of canine Chagas disease in Texas

Combination of anthelmintic drugs from different chemical groups has been proposed as alternative parasite control strategies where failure of individual drugs is documented. The main goal of the current trial was to compare the clinical anthelmintic efficacy of albendazole (ABZ) and ivermectin (IVM) given either separately or co-administered to lambs naturally infected with gastrointestinal nematodes resistant to both molecules. Seventy (70) Corriedale lambs naturally infected with multiple resistant gastrointestinal nematodes were involved in the efficacy trial: the animals were allocated into 7 experimental groups (n=10) and treated with either ABZ intravenously (iv) (ABZ(IV)), IVM(IV), ABZ(IV)+IVM(IV), ABZ intraruminally (ir) (ABZ(IR)), IVM subcutaneously (sc) (IVM(SC)) and ABZ(IR)+IVM(SC) or kept as untreated controls. The indirect estimation of the efficacy of the different treatments was performed by the faecal egg count reduction test (FECRT). Additionally, four animals randomly chosen from the untreated control and ABZ(IV,) IVM(IV) and ABZ(IV)+IVM(IV) experimental groups were sacrificed 15 days post-treatment to evaluate the efficacy against different adult resistant nematode parasites. The results were statistically compared by a non-parametric ANOVA (Kruskal-Wallis test). The following egg output reduction values were obtained: 73.4% (ABZ(IV)), 79.0% (IVM(IV)), 91.9% (ABZ(IV)+IVM(IV)), 43.5% (ABZ(IR)), 79.8% (IVM(SC)) and 70.8% (ABZ(IR)+IVM(SC)). The efficacy against Haemonchus spp. was 95.1 (ABZ(IV)), 99.3 (IVM(IV)) and 99.9% (ABZ(IV)+IVM(IV)), while the efficacy against Trichostrongylus colubriformis for the same treatment groups was 79.6, 100 and 99.9%. The data obtained on the assessment of the ABZ-IVM combination indicates that no potentiation synergism is observed. This work is complementary to a parallel study that demonstrated the lack of negative pharmacokinetic interactions between the two anthelmintics acting by different mode of action. Thus, an additive effect may be achieved against nematodes resistant to both compounds. Further work is required to understand the implications of potential pharmacokinetic/pharmacodynamic interactions between anthelmintics before drug combined formulations are developed to be introduced into the pharmaceutical market.     

Dose-dependent systemic exposure of albendazole metabolites in lambs

The gastrointestinal absorption of most drugs follows a first-order kinetics, whereby a constant fraction of the total drug is absorbed in each equal time interval. Although this related absorption principle is applicable to the most of the therapeutically used drugs, it remains unclear for poorly water-soluble compounds such as the benzimidazole anthelmintics in ruminants. The goal of the current work was to characterize the albendazole (ABZ) metabolites plasma disposition kinetics after ABZ administration at different dosages to nematode-infected lambs. Eighteen Corriedale lambs artificially infected with a resistant Haemonchus contortus strain were allocated into three groups and intraruminally treated with ABZ at either 5 (ABZ(5)), 15 (ABZ(15)) or 45 (ABZ(45)) mg/kg. Blood samples were collected up to 120 h post-treatment, and the collected plasma was analysed by high-performance liquid chromatography. The estimated pharmacokinetic parameters were statistically compared using parametric and nonparametric tests. None of the animals involved in the current trial showed any adverse events during the study. While ABZ parent drug was not recovered in the bloodstream, the area under the concentration vs time curve (AUC) of the active ABZ-sulphoxide (ABZSO) metabolite increased significantly (P<0.05) from 21.0 (ABZ(5)) up to 158.6 (ABZ(15)) and 389.7 μg·h/mL (ABZ(45)), which indicates some type of nonproportionality in the relationship between dose level and drug systemic exposure. The overall kinetic disposition of the inactive sulphone metabolite did not change after treatment at threefold the therapeutic ABZ dosage. However, significantly (P<0.05) higher AUC, C(max) and mean residence time values were observed after the administration of the highest dosage level. The higher dosages accounted for a significantly (P<0.05) enhancement of the ABZSO peak plasma concentration, which were obtained at delayed times post-treatment. High correlations between AUC(0-LOQ) and C(max) and nematode counts were observed, with Spearman's coefficients of -0.83 and -0.84, respectively. The results obtained in the current experiment show that increasing the dose of ABZ in sheep is clearly associated with enhanced plasma ABZ metabolites exposure. The data showed a nonproportionality on the gastrointestinal absorption of ABZ in nematode-infected lambs.     

Effect of the ionophore antibiotic monensin on the ruminal biotransformation of benzimidazole anthelmintics

The benzimidazole (BZD) anthelmintics, netobimin (NTB) pro-drug and albendazole sulphoxide (ABZSO) are reduced to albendazole (ABZ) by ruminal microflora. The aim of the current work was to evaluate the influence of the ionophore monensin (MON) on the in vitro biotransformation of NTB and ABZSO by sheep ruminal fluid. Ruminal fluid, collected from Corriedale sheep, was preincubated (24 h) either without (control) or with known MON concentrations (0.5, 1.5 and 3.0 microg/mL) at 38 degrees C under a CO2 atmosphere. Afterwards, aliquots from both MON-pretreated and control ruminal fluid samples were incubated (30 and 60 min) with 2 microg/mL of either NTB or ABZSO. Incubated samples were chemically extracted and analysed by High Performance Liquid Chromatography to quantify the metabolites formed. The rate of ABZ production after 30 min of NTB incubation with control ruminal fluid was 0.023 microg/min. Conversely, the rates of ABZ formation were significantly (P<0.05) lower (0.009, 0.011 and 0.013 microg/min) when NTB was incubated with ruminal fluid pretreated with MON (at 0.5, 1.5 and 3.0 microg/mL, respectively). After both incubation periods, the reduction of ABZSO to ABZ was 22 to 70% lower when the ruminal fluid was preincubated with the different MON concentrations. The lower ABZ production observed in the presence of MON may result in a modified availability of this molecule in the gastrointestinal (GI) tract and hence, on its anthelmintic efficacy against GI nematodes.     

Effect of single and divided dose administration on thepharmacokinetics of albendazole in sheep and goat

The pharmacokinetics of albendazole were studied in sheep and goats following single and divided doseadministration at nematocidal and flukicidal dose rates. The disposition curves of the metabolites indicated increased uptake of the drug both in sheep and goats at divided dose schedules compared to single dose administration (P<0.05). The increased bioavailability of benzimidazole anthelmintics in divided dose schedules could improve their efficacy and help in extending their lives.     

The inability of tapeworm Hymenolepis diminuta and fluke Dicrocoelium dendriticum to metabolize praziquantel

Biotransformation enzymes can, to a certain extent, protect parasitic worms against the toxic effects of anthelmintics and can contribute to drug-resistance development. The objective of our work was (1) to find and identify phase I and II metabolites of the anthelmintic praziquantel (PZQ) formed by the lancet fluke (Dicrocoelium dendriticum) and the rat tapeworm (Hymenolepis diminuta) and (2) to compare PZQ metabolites in helminths with PZQ biotransformation in rat as host species. Ultra high performance liquid chromatography/tandem mass spectrometry (UHPLC/MS/MS) was used for this purpose. During in vitro incubations, mitochondria-like and microsomes-like fractions (prepared from homogenates of adult worms or from rat liver homogenate) were incubated with 10 and 100 μM PZQ. Liquid/liquid extraction was used for samples during in vitro experiments. In the ex vivo study, living D. dendriticum and H. diminuta adults were incubated in RPMI-1640 medium in the presence of 50 nM or 100 nM PZQ for 24h. After incubation, the worms were removed from the medium and homogenized. Homogenates of worms, medium from the incubation of worms or rat hepatocytes and rat urine (collected during 24h after oral PZQ administration) were separately extracted using solid-phase extraction. The results showed that both D. dendriticum and H. diminuta enzymatic systems are not able to metabolize PZQ. On the other hand, thirty one different phase I and four phase II PZQ metabolites were detected in rat samples using UHPLC/MS/MS analyses. These results show that our experimental helminths, as the members of tapeworm and fluke groups of parasites, are not able to deactivate PZQ, and that the biotransformation enzymes of the studied helminths do not contribute to PZQ-resistance.     

Import and efflux of flubendazole in Haemonchus contortus strains susceptible and resistant to anthelmintics

Drug entry into the body of a helminth is a key factor in the efficacy of anthelmintics. The present project was designed to study the ex vivo uptake and efflux of the benzimidazole anthelmintic flubendazole (FLU) in four strains of H. contortus: the ISE strain (fully susceptible to anthelmintics), the ISE-S strain (resistant to ivermectin), the BR strain (resistant to benzimidazoles) and the WR strain (multi-resistant). The transport of FLU between dead and living nematodes was also compared as well as the effect of verapamil, an inhibitor of the main efflux ABCB1 transporter (P-glycoprotein), on FLU accumulation in nematodes. The obtained results showed that FLU is able to effectively enter H. contortus adults due to high FLU lipophilicity. Passive diffusion is probably the only mechanism in both FLU import and efflux from nematodes. No differences in FLU transport were found among four H. contortus strains with different sensitivity to anthelmintics. No active FLU efflux from H. contortus and no effect of verapamil were observed, indicating that H. contortus cannot protect itself against FLU by the active removal of this anthelmintic from its body.     

Chiral behaviour of the metabolite albendazole sulphoxide in sheep, goats and cattle

Three sheep, three goats and three cattle were dosed orally with 5.0, 7.5 and 10 mg albendazole kg-1 bodyweight, respectively. Blood samples were taken at intervals for 48 hours after administration. The enantiomeric ratio of the metabolite albendazole sulphoxide (SO.ABZ) was determined by liquid chromatography on chiral stationary phases. At To, the plasma concentration ratio (+)SO.ABZ/(-)SO.ABZ was estimated at 3.0 in sheep, 1.5 in goats and 4.0 in cattle. The proportion of the (+) enantiomer then increased linearly as a function of time during the course of the kinetics. In comparison to the area under the curve for total SO.ABZ, the (+) enantiomer represented 86 per cent in sheep, 80 per cent in goats and 91 per cent in cattle. The specific behaviour of the two enantiomers is probably the result of the enantioselectivity of the flavine adenosine dinucleotide and cytochrome P450 dependent enzymatic systems which are involved in the sulphoxidation and the sulphonation of ABZ.     

Pharmacokinetics of albendazole sulfoxide enantiomers administered in racemic form and separately in rats

The pharmacokinetic behaviour of albendazole sulfoxide (ABZSO) enantiomers was studied in rats after the oral administration of 10 mg/kg of rac-ABZSO, 5 mg/kg of (-)-ABZSO or 5 mg/kg of (+)-ABZSO. The disposition profiles of ABZSO enantiomers were similar in all treatments, but the calculated area under the curve for the (-)-ABZSO was higher in all cases compared with (+)-ABZSO. The results suggest that there is no chiral inversion of ABZSO enantiomers. After the administration of rac-ABZSO, 17.2% of the total dose was recovered in urine as albendazole ABZ (0.1%), albendazole sulfone ABZSO(2) (0.3%), albendazole 2-aminosulfone (ABZ-SO(2)NH(2)) (3.1%) and ABZSO (13.7%). The ratio (+) to (-) was similar in urine (1.6) and blood (1.7).     

Metabolism and depletion of albendazole in the muscle tissue of channel catfish following oral treatment

The residue depletion of albendazole (ABZ) and its metabolites was studied in channel catfish muscle tissue. Channel catfish were dosed once with 10 mg/kg ABZ via stomach tube with manual restraint. Muscle tissue samples were collected at 8, 16, 24, 48, 72, 96 and 120 h postdose. A high-performance liquid chromatographic method was used to assay ABZ and its major metabolites: ABZ sulfoxide (ABZ-SO), ABZ sulfone (ABZ-SO2) and ABZ aminosulfone (ABZ-2-NH2SO2) in the muscle tissue. The results indicate that ABZ and ABZ-SO were present in low concentrations, i.e. <15 and <10 microg/kg, respectively, at 8 h postdose in catfish muscle with and without skin. ABZ-SO2 was present at 1 microg/kg concentration levels until 48 h in muscle alone and 72 h in muscle with skin. ABZ-2-NH2SO2 was not detected at any withdrawal periods.     

Comparative plasma disposition kinetics of albendazole, fenbendazole, oxfendazole and their metabolites in adult sheep

The comparative plasma disposition kinetics of albendazole (ABZ), fenbendazole (FBZ) and oxfendazole (OFZ) following their oral administration (5 mg/kg) to adult sheep was characterized. Jugular blood samples were taken serially over a 144 h period and plasma was analysed by high performance liquid chromatography (HPLC) for ABZ, ABZ sulphoxide (ABZSO) and ABZ sulphone (ABZSO₂) (ABZ treatment), and for FBZ, OFZ and FBZ sulphone (FBZSO₂) (FBZ and OFZ treatments). While the ABZ parent drug was not detected at any time post-treatment, ABZSO and ABZSO₂ were the analytes recovered in plasma, after oral administration of ABZ to sheep. The active ABZSO metabolite was the main analyte recovered in plasma (between 0.25 and 60h post-treatment), accounting for 71 % of the total AUC. FBZ, OFZ and FBZSO₂ were the analytes detected in plasma following the oral administration of both FBZ and OFZ to sheep. Low concentrations of FBZ were found in plasma between 4 (FBZ treatment) or 8 h (OFZ treatment) and 72 h post-treatment. The plasma profile of each analyte followed a similar pattern after both treatments; OFZ being the main component detected in plasma. The plasma disposition of ABZ metabolites was markedly different to that of FBZ derivatives. ABZSO exhibited faster absorption and a higher C_max than OFZ (both treatments). Furthermore, while ABZSO declined relatively rapidly in plasma reaching non-detectable concentrations at 60 h post-ABZ administration, OFZ was found in plasma for up to 120 (FBZ treatment) and 144 h (OFZ treatment). The extended detection of OFZ in plasma in both treatments correlated with the prolonged t_1/2β (18 h) and mean residence time (MRT) (30–33 h) obtained for this metabolite compared to those of ABZSO (t_1/2β= (7.0 h); MRT= 12.5 h). These differences between the disposition of ABZ and FBZ metabolites may account for differences in their patterns of efficacy and tissue residues.