Metabolism and residue depletion of albendazole and its metabolites in rainbow trout, tilapia and Atlantic salmon after oral administration

Metabolic and residue depletion profiles of albendazole (ABZ) and its major metabolites in three fish species, rainbow trout, tilapia and Atlantic salmon are reported. Based on these profiles, similarities (or dissimilarities) between species will determine the potential to group fish species. ABZ at 10 mg/kg body weight was incorporated into fish food formulated in a gelatin base or in gel capsule and fed as a single dose to six fish from each species. Rainbow trout were held three each in a partitioned 600-L tank. Tilapia and Atlantic salmon were housed in separate 20-L tanks. Samples of muscle with adhering skin were collected at 8, 12, 18, 24, 48, 72, and 96 h postdose from trout kept at 12 degrees C, at 4, 8, 12, 24, 48, 72, 96, 120, and 144 h postdose from tilapia kept at 25 degrees C and at 8, 14, 24, 48, 72, and 96 h postdose from Atlantic salmon kept at 15 degrees C. The samples were homogenized in dry ice and subjected to extraction and cleanup procedures. The final extracts were analyzed for parent drug ABZ and its major metabolites, albendazole sulfoxide (ABZ-SO), albendazole sulfone (ABZ-SO2) and albendazole aminosulfone using high-performance liquid chromatography with fluorescence detection. ABZ was depleted by 24 h in trout and tilapia and by 48 h in salmon; ABZ-SO, a pharmacologically active metabolite, was depleted by 48 h in tilapia, by 72 h in rainbow trout and was present until 96 h in salmon; and low levels of ABZ-SO2 and albendazole aminosulfone, both inactive metabolites, were detectable at least till 96 h in all three fish species.     

The disposition of albendazole in sheep

Albendazole (ABZ) was administered intraruminally at 4.75 mg/kg to sheep fitted with a permanent bile-duct cannula to determine if its metabolites might contribute to its flukicidal action. ABZ metabolism was consistent with first-pass clearance by the liver, resulting in ABZ sulphoxide (ABZ-SO) and ABZ sulphone (ABZ-SO2) being present in plasma at maximum concentrations (mean Cmax +/- SD) of 2.0 +/- 0.2 micrograms/ml and 0.4 +/- 0.1 micrograms/ml after 8 +/- 3 h and 24 +/- 5 h, respectively. ABZ-SO, but more particularly ABZ-SO2, appeared to bind to plasma proteins but their clearance rates from plasma were similar. Biliary ABZ metabolites were mainly unconjugated ABZ-SO and 2OH-ABZ-SO (8.0% dose) or conjugated glucuronide and sulphate esters (6.3% dose) mainly of 2OH-ABZ-SO and 2OH-ABZ-SO2. The concentration of the major biliary metabolite, unconjugated ABZ-SO, followed a similar time profile to that of ABZ-SO in plasma except that Cmax was much higher (6.2 +/- 2.2 micrograms/ml). Intraruminal administration of ABZ reduced bile flow rate by 30% which may be attributable to an inhibitory effect of ABZ on microtubule formation in hepatic secretory cells. It is suggested that ABZ is sequestered in the liver. This is unlikely to contribute to its flukicidal action, which is probably attributable to ingestion of ABZ-SO from bile and blood by the fluke.     

In vitro kinetics of hepatic albendazole sulfoxidation in channel catfish (Ictalurus punctatus), tilapia (Oreochromis sp.), rainbow trout (Oncorhynchus mykiss) and induction of EROD activity in ABZ-dosed channel catfish

Liver microsomes from market-size ( n  = 6) rainbow trout, channel catfish and tilapia were used to investigate in vitro biotransformation kinetics of albendazole (ABZ). ABZ was transformed to a single metabolite, ABZ sulfoxide (ABZ-SO). Catfish displayed the highest maximal velocity ( V _max = 264.0 ± 58.6 pmols ABZ-SO/min/mg protein) followed by tilapia (112.3 ± 8.2) and rainbow trout (73.3 ± 10.3). V _max in catfish was significantly different ( P  < 0.05) from the other two species. Michaelis–Menten constant ( K _m) values (μ m ) varied significantly among the species: rainbow trout (3.9 ± 0.5), tilapia (9.2 ± 1.7) and catfish (22.0 ± 3.2). However, V _max/ K _m ratios showed no difference among the three species, making them equally efficient performing this phase I biotransformation reaction. In a second series of experiments, channel catfish ( n  = 6 per treatment) were dosed in vivo with gel-food containing ABZ (10 mg/kg, p.o.). Fish were killed at 24, 48, 72 and 120 h after dosage. Control fish were fed ABZ-free feed. Induction of ethoxyresorufin-o-deethylase activity was significant ( P  < 0.05) in all ABZ-dosed treatments as compared with controls.     

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.     

Plasma disposition and faecal excretion of oxfendazole, fenbendazole and albendazole following oral administration to donkeys

Fenbendazole (FBZ), oxfendazole (fenbendazole sulphoxide, FBZSO), and albendazole (ABZ) were administered orally to donkeys at 10mg/kg bodyweight. Blood and faecal samples were collected from 1 to 120 h post-treatment. The plasma and faecal samples were analysed by high performance liquid chromatography (HPLC). The parent molecule and its sulphoxide and sulphone (FBZSO(2)) metabolites did not reach detectable concentrations in any plasma samples following FBZ administration. ABZ was also not detected in any plasma samples, but its sulphoxide and sulphone metabolites were detected, demonstrating that ABZ was completely metabolised by first-pass mechanisms in donkeys. Maximum plasma concentrations (C(max)) of FBZSO (0.49microg/mL) and FBZSO(2) (0.60microg/mL) were detected at (t(max)) 5.67 and 8.00h, respectively, following administration of FBZSO. The area under the curve (AUC) of the sulphone metabolite (10.33microg h/mL) was significantly higher than that of the parent drug FBZSO (5.17microg h/mL). C(max) of albendazole sulphoxide (ABZSO) (0.08g/mL) and albendazole sulphone (ABZSO(2)) (0.04microg/mL) were obtained at 5.71 and 8.00h, respectively, following ABZ administration. The AUC of the sulphoxide metabolite (0.84microg h/mL) of ABZ was significantly higher than that of the sulphone metabolite (0.50microg h/mL). The highest dry-faecal concentrations of parent molecules were detected at 32, 34 and 30h for FBZSO, FBZ and ABZ, respectively. The sulphide metabolite was significantly higher than the parent molecule after FBZSO administration. The parent molecule was predominant in the faecal samples following FBZ administration. After ABZ administration, the parent molecule was significantly metabolised, probably by gastrointestinal microflora, to its sulphoxide metabolite (ABZSO) that showed a similar excretion profile to the parent molecule in the faecal samples. The AUC of the parent FBZ was significantly higher than that of FBZSO and ABZ in faeces. It is concluded that the plasma concentration of FBZSO was significantly higher than that of FBZ and ABZ. Although ABZ is not licensed for use in Equidae, its metabolites presented a greater plasma kinetic profile than FBZ which is licensed for use in horses. A higher metabolic capacity, first-pass effects and lower absorption of benzimidazoles in donkeys decrease bioavailability and efficacy compared to ruminants.     

Gastrointestinal distribution of albendazole metabolites following netobimin administration to cattle: relationship with plasma disposition kinetics

The gastrointestinal (GI) distribution and plasma disposition kinetics of alberidazole (ABZ) metabolites after oral administration of netobirnin (NTB) to cattle were studied. Eight Holstein steers (150–180 kg) were surgically fitted with permanent cannulae in the rumen, abomasum and ileum. After post-surgical recovery, the ariinials were treated orally with a suspension of neto1)imin zwitterion (400 mg/ml) at 20 nig/kg. Jugular blood and ruminal, abomasal arid ileal fluid samples were taken serially over a 96 h period and analysed by HPLC for NTB and its metabolites, including ABZ, ABZ sulphoxide (ABZSO), AH% sulphone (ABZSO?) and amino-albendazole sulphone (NHp4BZSOy). N T B parent drug was only fonnd in the G I tract and for only 12–18 h post-treatment. ABZSO and ABZSOp were the main metabolites found in plasma, being present for 30–36 h. These metabolites were exchanged between plasma and different GI fluids and were greatly concentrated in the abomasum. This phenornenori may account for the presence of ABZ, ABZSO and ABZSO? in the GI tract f'or 72 h post-treatment despite the fact that ABZ was riot detected in plasma and ABZSO and ABZSO.;, were detected for only 30–36 h in plasma. The presence o f ABZ and ABZSO in the abomasum and intestine for this extended period of time is probably relevant for anthelmintic efficacy against GI parasites. The NH₂ ABZSO₂ metabolite was detected in plasma, abomasum and ileum and its disposition kinetics were characterized for the first time.     

Enhanced Plasma Availability of the Metabolites of Albendazole in Fasted Adult Sheep

Lifschitz, A., Virkel G., Mastromarino, M. and Lanusse C., 1997. Enhanced plasma availability of the metabolites of albendazole in fasted adult sheep. Veterinary Research Communications, 21 (3), 201-211The influence of fasting prior to treatment and of dosing rate on the plasma availability and disposition kinetics of albendazole (ABZ) and its sulphoxide (ABZSO) and sulphone (ABZSO2) metabolites was studied in adult sheep grazing on pasture. A micronized suspension of ABZ was administered orally at either 7.5 mg/kg (group A) or 11.3 mg/kg (group C) to sheep fed ad libitum, and at 7.5 mg/kg to sheep subjected to a 24 h fasting period prior to treatment (group B). Blood samples were taken serially over 96 h after treatment, and the plasma was analysed for ABZ and its metabolites by high-performance liquid chromatography. ABZSO and ABZSO2 were recovered from the plasma. Fasting induced marked modifications in the pharmacokinetic behaviour of the ABZ metabolites in sheep. An extended absorption process, with a delayed peak concentration in the plasma, was observed for both metabolites in the fasted sheep. Significantly higher area under the curve (AUC) and peak plasma concentration (Cmax) values were obtained for both metabolites in the fasted animals compared to those fed ad libitum. Delayed elimination with prolonged detection in plasma was also observed in the fasted sheep. Treatment with ABZ at 7.5 mg/kg in the starved animals resulted in bioequivalence to the administration of the compound at a 50% higher dose rate (11.3 mg/kg) in the fed animals. It is suggested that fasting enhances ABZ dissolution and absorption by delaying its passage down the digestive tract.     

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.     

Residue depletion of thiamphenicol in the sea-bass

The residue depletion of thiamphenicol (TAP) was investigated in the sea-bass (Dicentrarchus labrax) after 5 days' treatment with medicated food at a dose of 15 or 30 mg/kg bw/day. Fish were sampled for blood and muscle + skin from 3 h until 14 days after treatment. Thiamphenicol concentrations were assayed by high performance liquid chromatography. Thiamphenicol concentrations measured 3 h after stopping treatment were 0.77 microg/mL and 0.91 (15 mg/kg dose) or 1.32 microg/mL and 1.47 microg/g (30 mg/kg dose), in plasma and muscle + skin, respectively. After a withdrawal of 3 days, plasma and tissue concentrations were: 0.08 microg/mL and 0.03 microg/g (lower dose) or 0.12 microg/mL and 0.06 microg/g (higher dose), respectively. Thiamphenicol was not detectable either in plasma or in tissues on days 7, 10 and 14 following withdrawal of the medicated food. Based on maximum residue levels (MRL) for TAP in fin fish, established at 50 microg/kg for muscle and skin in natural proportions, a withdrawal period of 5 and 6 days is proposed, after treatment at 15 or 30 mg/kg of TAP with medicated feed pellets, respectively, to avoid the presence of violative residues in the edible tissues of the sea-bass.     

Pharmacokinetic profiles of netobimin metabolites after oral administration of zwitterion and trisamine formulations of netobimin to cattle

Pharmacokinetic profiles of the major metabolites of netobimin were investigated in calves after oral administration of the compound (20 mg/kg) as a zwitterion suspension and trisamine salt solution in a two-way cross-over design. Blood samples were taken serially over a 72-h period and plasma was analysed by HPLC for netobimin (NTB) and its metabolites, including albendazole (ABZ), albendazole sulphoxide (ABZSO) and albendazole sulphone (ABZSO2). NTB was occasionally detected in plasma between 0.5 and 1.0 h post-treatment. ABZ was not detectable at any time. ABZSO was detected from 0.5-0.75 h up to 32 h post-administration, with a Cmax for the zwitterion suspension of 1.21 +/- 0.13 micrograms/ml and AUC of 18.55 +/- 1.45 micrograms.h/ml, respectively, which were significantly higher (P less than 0.01) than the Cmax (0.67 +/- 0.12 micrograms/ml) and AUC (8.57 +/- 0.91 micrograms.h/ml) for the trisamine solution. ABZSO2 was detected in plasma between 0.75 and 48 h post-administration. The zwitterion suspension resulted in a Cmax (2.91 +/- 0.10 micrograms/ml) and AUC (51.67 +/- 1.95 micrograms.h/ml) for ABZSO2, which were significantly higher (P less than 0.01) than those obtained for the trisamine solution (Cmax = 1.67 +/- 0.11 micrograms/ml and AUC = 22.77 +/- 1.09 micrograms.h/ml). The ratio of AUC for ABZSO2/ABZSO was 2.92 +/- 0.26 (zwitterion) and 2.80 +/- 0.20 (trisamine). The MRT for ABZSO2 was significantly longer (P less than 0.01) after treatment with the zwitterion suspension than after treatment with the trisamine solution.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

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.     

Disposition kinetics of albendazole and metabolites in laying hens

Bistoletti, M., Alvarez, L., Lanusse, C., Moreno, L. Disposition kinetics of albendazole and metabolites in laying hens. J. vet. Pharmacol. Therap.  36 , 161–168. An increasing prevalence of roundworm parasites in poultry, particularly in litter‐based housing systems, has been reported. However, few anthelmintic drugs are commercially available for use in avian production systems. The anthelmintic efficacy of albendazole (ABZ) in poultry has been demonstrated well. The goal of this work was to characterize the ABZ and metabolites plasma disposition kinetics after treatment with different administration routes in laying hens. Twenty‐four laying hens Plymouth Rock Barrada were distributed into three groups and treated with ABZ as follows: intravenously at 10 mg/kg (ABZ i.v.); orally at the same dose (ABZ oral); and in medicated feed at 10 mg/kg·day for 7 days (ABZ feed). Blood samples were taken up to 48 h posttreatment (ABZ i.v. and ABZ oral) and up to 10 days poststart feed medication (ABZ feed). The collected plasma samples were analyzed using high‐performance liquid chromatography. ABZ and its albendazole sulphoxide (ABZSO) and ABZSO₂ metabolites were recovered in plasma after ABZ i.v. administration. ABZ parent compound showed an initial concentration of 16.4 ± 2.0 μg/mL, being rapidly metabolized into the ABZSO and ABZSO₂ metabolites. The ABZSO maximum concentration (C_max) (3.10 ± 0.78 μg/mL) was higher than that of ABZSO₂C_max (0.34 ± 0.05 μg/mL). The area under the concentration vs time curve (AUC) for ABZSO (21.9 ± 3.6 μg·h/mL) was higher than that observed for ABZSO₂ and ABZ (7.80 ± 1.02 and 12.0 ± 1.6 μg·h/mL, respectively). The ABZ body clearance (Cl) was 0.88 ± 0.11 L·h/kg with an elimination half‐life (T_1/2el) of 3.47 ± 0.73 h. The T_1/2el for ABZSO and ABZSO₂ were 6.36 ± 1.50 and 5.40 ± 1.90 h, respectively. After ABZ oral administration, low ABZ plasma concentrations were measured between 0.5 and 3 h posttreatment. ABZ was rapidly metabolized to ABZSO (C_max, 1.71 ± 0.62 μg/mL) and ABZSO₂ (C_max, 0.43 ± 0.04 μg/mL). The metabolite systemic exposure (AUC) values were 18.6 ± 2.0 and 10.6 ± 0.9 μg·h/mL for ABZSO and ABZSO₂, respectively. The half‐life values after ABZ oral were similar (5.91 ± 0.60 and 5.57 ± 1.19 h for ABZSO and ABZSO₂, respectively) to those obtained after ABZ i.v. administration. ABZ was not recovered from the bloodstream after ABZ feed administration. AUC values of ABZSO and ABZSO₂ were 61.9 and 92.4 μg·h/mL, respectively. The work reported here provides useful information on the pharmacokinetic behavior of ABZ after both i.v. and oral administrations in hens, which is a useful first step to evaluate its potential as an anthelmintic tool for use in poultry.     

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).     

Pharmacokinetics of cefovecin in cats

The pharmacokinetics of the novel cephalosporin cefovecin were investigated in a series of in vivo, ex vivo and in vitro studies following administration to adult cats at 8 mg/kg bodyweight. Bioavailability and pharmacokinetic parameters were determined in a cross-over study after intravenous (i.v.) and subcutaneous (s.c.) injections. [14C]cefovecin was used to evaluate excretion for 21 days after s.c. administration. Protein binding was determined in vitro in feline plasma and ex vivo in transudate from cats surgically implanted with tissue chambers. After s.c. administration, cefovecin was characterized by rapid absorption with mean peak plasma concentrations of 141+/-12 microg/mL being achieved within 2 h of s.c. injection with full bioavailability (99%). The mean elimination half-life was 166+/-18 h. After i.v. administration, volume of distribution was 0.09+/-0.01 L/kg and mean plasma clearance was 0.35+/-0.04 mL/h/kg. Approximately 50% of the administered radiolabelled dose was eliminated over the 21-day postdose period via urinary excretion and up to approximately 25% in faeces. In vitro and ex vivo plasma protein binding ranged from 99.8% to 99.5% over the plasma concentration range 10-100 microg/mL. Ex vivo protein binding in transudate was as low as 90.7%. From 8 h postdose, concentrations of unbound (free) cefovecin in transudate were consistently higher than in plasma, with mean unbound cefovecin concentrations being maintained above 0.06 microg/mL (MIC90 of Pasteurella multocida) in transudate for at least 14 days postdose. The slow elimination and long-lasting free concentrations in extracellular fluid are desirable pharmacokinetic attributes for an antimicrobial with a 14-day dosing interval.     

FASTING-INDUCED CHANGES TO THE PHARMACOKINETIC BEHAVIOUR OF ALBENDAZOLE AND ITS METABOLITES IN CALVES

The influence of fasting on the bioavailability and disposition kinetics of albendazole (ABZ) and its metabolites in cattle was investigated. ABZ (10 mg/kg) was given by intraruminal (i.r.) (Experiment 1) and intravenous (i.v.) (Experiment 2) administration to Holstein calves either fed ad libitum (control) or subjected to a 48 h fasting period (fasted group) prior to treatment. The rate of passage of digesta through the gastrointestinal (GI) tract was evaluated by measurement of cobalt faecal excretion following the oral administration of the sodium-cobalt-ethylendiamine-tetracetic acid complex to calves subjected to the feeding conditions above described. Jugular blood and abomasal fluid (via cannula) samples were collected over 120 h post-treatment; samples were analysed by high performance liquid chromatography (HPLC) for ABZ, ABZ sulphoxide (ABZSO) and ABZ sulphone (ABZSO₂). Fasting the animals prior to the i.r. treatment resulted in pronounced modifications to the plasma and abomasal fluid disposition kinetics of ABZ and its metabolites. A greater extent of GI absorption with significantly higher C_max (150%) and AUC (310%) values for ABZSO in plasma, was observed in fasted compared to fed animals following the i.r. administration of ABZ. Extended detection of ABZ metabolites resulting in significantly longer plasma t_½el and MRT was also obtained in fasted compared to fed calves. These results correlated with the substantially enhanced availability of ABZ and its metabolites (AUCs over 200% greater) in the abomasal fluid of the fasted animals. Fasting did not induce changes to the plasma disposition of either ABZ or its metabolites after the i.v. treatment. The digesta passage rate, measured by the amount of cobalt excreted in faeces, was significantly lower in fasted compared to animals fed ad libitum. A delayed GI transit time that decreases the rate of passage of the drug down the digestive tract, may have accounted for enhanced ABZ dissolution and absorption in fasted compared to fed calves. The findings reported in this article show that fasting prior to treatment notably affects the bioavailability and disposition kinetics of ABZ and its metabolites in cattle.     

Pharmacokinetics and tissue residues of pefloxacin and its metabolite norfloxacin in broiler chickens

1. The pharmacokinetics of pefloxacin and its active metabolite norfloxacin were investigated in chickens after a single oral administration of pefloxacin at a dosage of 10 mg/kg. To characterise the residue pattern, another group of chickens was given 10 mg of pefloxacin/kg body once daily for 4 d by oral route; the tissue concentrations of pefloxacin and norfloxacin were determined at 1, 5 and 10 d after the last administration of the drug. 2. The concentrations of pefloxacin and norfloxacin in plasma and tissues were determined by HPLC assay. The limit of detection for pefloxacin and norfloxacin was 0.03 microg/ml in plasma or microg/g in tissue. 3. The plasma concentration-time data for pefloxacin and norfloxacin were characteristic of a one-compartment open model. The elimination half-life, maximum plasma drug concentration, time to reach maximum plasma drug concentration and mean residence time of pefloxacin were 8.74 +/- 1.48 h, 3.78 +/- 0.23 microg/ml, 3.33 +/- 0.21 h and 14.32 +/- 1.94 h, respectively, whereas the respective values of these variables for norfloxacin were 5.66 +/- 0.81 h, 0.80 +/- 0.07 microg/ml, 3.67 +/- 0.21 h and 14.44 +/- 0.97 h. 4. Pefloxacin was metabolised to norfloxacin to the extent of 22%. 5. The concentrations of pefloxacin (microg/g) 24 h after the fourth dose of the drug declined in the following order: liver (3.20 +/- 0.40) > muscle (1.42 +/- 0.18) > kidney (0.69 +/- 0.04) > skin and fat (0.06 +/- 0.02). Norfloxacin was also detectable in all the tissues analysed except muscle. No drug and/or its metabolite was detectable in tissues except skin and fat 5 d after the last administration. The concentrations of pefloxacin and norfloxacin in skin and fat 10 d after the last dose of pefloxacin were 0.04 +/- 0.02 and 0.03 +/- 0.01 microg/g, respectively.     

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.     

Albendazole treatment in laying hens: Egg residues and its effects on fertility and hatchability

This work characterized the egg residual concentrations of albendazole (ABZ ) and its sulphoxide (ABZSO ) and sulphone (ABZSO ₂) metabolites and evaluated their effect on egg fertility and hatchability after ABZ treatments to laying hens. Seventy hens were allocated in groups: Group‐1 was the control without treatment; Group‐2 received a single ABZ oral dose (10 mg/kg); Group‐3, ‐4 and ‐5 were treated with ABZ in medicated feed over 7 days at 10, 40, or 80 mg kg^?1 day^?1, respectively. Eggs were analyzed to determine the ABZ /metabolite level by HPLC or subjected to incubation to evaluate the fertility and hatchability. Only ABZSO and ABZSO ₂ metabolites were quantified in egg after ABZ single oral administration with maximum concentrations of 0.47 ± 0.08 and 0.30 ± 0.07 μg/ml, respectively. ABZ and its metabolites were found in eggs after 7‐day ABZ treatments. The egg residue exposure estimated as AUC s (areas under the concentration vs . time curve) were 100.5 (ABZ ), 56.3 (ABZSO ) and 141.3 μg hr g^?1 (ABZSO ₂). ABZ administration did not affect the egg fertility at any dosages. Egg hatchability was not affected by ABZ treatment at 10 mg/kg in medicated feed, but it decreased when the dose was 4–8 times higher. These results should be considered when ABZ is used for deworming laying hens.     

Azithromycin metabolite identification in plasma,bile, and tissues of the ball python (Python regius)

Azithromycin is the first of a class of antibiotics classified as azalides. Six ball pythons (Python regius) were given a single dose of azithromycin at 10 mg/kg p.o. and i.v. in a crossover design. Serial blood samples were collected for unchanged azithromycin and to determine, if possible, the structure and number of circulating azithromycin metabolites. After a 4-month wash-out period, the snakes were given azithromycin p.o. as a single dose of 10 mg/kg for the study of azithromycin metabolism and metabolite tissue distribution. Bile, liver, lung, kidney, and skin samples were analyzed for the metabolites identified from the first experiment. Unchanged azithromycin accounted for 80, 68, and 60% of the total material at 12, 24, and 48 h postadministration in plasma, independent of route of administration. At both 24 and 72 h postadministration, azithromycin accounted for 70% of total azithromycin- associated material in bile. In liver and kidney, unchanged azithromycin accounted for 40% of the total azithromycin-associated material; this doubled in lung and skin. Fifteen metabolites were positively or tentatively identified in plasma, bile, or tissues of all snakes. Four of these possible metabolites: 3'-desamine-3-ene-azithromycin, descladinose dehydroxy-2-ene-azithromycin, 3'-desamine-3-ene descladinose-azithromycin, and 3'-N-nitroso,9a-N-desmethyl-azithromycin are unique to this species. Descladinose-azithromycin, 3'-N-desmethyl,9a-N-desmethyl-azithromycin, and 3'-N-desmethyl, 3'-O-desmethyl-azithromycin were the only metabolites identified in skin. Kidney tissue contained a greater number of metabolites than liver tissue, with 3'-N-didesmethyl-azithromycin being identified only in the kidney. Compared with the dog and cat, a greater number of metabolites were identified in ball python plasma. The percentage of unchanged azithromycin in bile is not different between the three species.