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).     

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.     

Aspects of the Pharmacokinetics of Albendazole Sulphoxide in Sheep

The plasma disposition kinetics of albendazole sulphoxide (ABZSO), ((+)ABZSO and (–)ABZSO) and its sulphone metabolite (ABZSO₂) were investigated in adult sheep. Six Corriedale sheep received albendazole sulphoxide by intravenous injection at 5 mg/kg live weight. Jugular blood samples were taken serially for 72 h and the plasma was analysed by high-performance liquid chromatography (HPLC) for albendazole (ABZ), ABZ sulphoxide (ABZSO) and albendazole sulphone (ABZSO₂). Albendazole was not detected in the plasma at any time after the treatment, ABZSO and ABZSO₂ being the main metabolites detected between 10 min and 48 h after treatment. A biexponential plasma concentration versus time curve was observed for both ABZSO and ABZSO₂ following the intravenous treatment. The plasma AUC values for ABZSO and ABZSO₂ were 52.0 and 10.8 (g.h)/ml, respectively. The ABZSO₂ metabolite was measurable in plasma between 10 min and 48 h after administration of ABZSO, reaching a peak concentration of 0.38 g/ml at 7.7 h after treatment. Using a chiral phase-based HPLC method, a biexponential plasma concentration versus time curve was observed for both ABZSO enantiomers. The total body clearance was higher for the (–) than for the (+) enantiomer, the values being 270.6 and 147.75 (ml/h)/kg, respectively. The elimination half-life of the (–) enantiomer was shorter than that of the (+) enantiomer, the values being 4.31 and 8.33 h, respectively. The enantiomeric ratio (+)ABZSO/(–)ABZSO at t ₀ was close to unity. However, the ratio in the plasma increased with time.     

In vitro ruminal biotransformation of benzimidazole sulphoxide anthelmintics: enantioselective sulphoreduction in sheep and cattle

The comparative in vitro sulphoreduction of the (+) and (-) enantiomers of albendazole sulphoxide (ABZSO) and oxfendazole (OFZ) by ruminal fluid obtained from sheep and cattle, was investigated, under anaerobic conditions, in this study. Ruminal fluid samples were obtained from Holstein steers fitted with a permanent rumen fistula and from Corriedale lambs via an oesophageal tube. Albendazole sulphoxide, incubated as either the racemic (rac) mixture or as each individual enantiomeric form, was extensively sulphoreduced to form albendazole (ABZ) by ruminal fluid from both species. The concentrations of ABZ formed at different incubation times were between 55 and 158% greater after the incubation of cattle ruminal fluid with (+) ABZSO, compared with that produced when (-) ABZSO was the incubated substrate. Similarly, the concentrations of ABZ were 1.3--3.0-fold higher when (+) ABZSO was incubated with sheep ruminal fluid. Significantly higher rates of depletion were observed for the (+) enantiomeric form when ABZSO was incubated with ruminal fluid from both species. The rates of ABZ formation from both ABZSO enantiomeric forms were significantly higher in sheep compared with cattle ruminal fluid. Fenbendazole (FBZ) was the metabolite formed after the incubation of the racemic form of OFZ with ruminal fluid obtained from both species. The metabolic profile of both OFZ enantiomers followed a similar pattern to that observed for ABZSO enantiomers. A bi-directional chiral inversion of one enantiomer into its antipode was observed. The (+) enantiomer appeared in the incubation medium when (-) ABZSO was the incubated substrate, and also the (-) antipode was detected after (+) ABZSO incubation with ruminal fluid obtained from both species. The results reported here demonstrate an enantioselective ruminal sulphoreduction of ABZSO and OFZ (substrate enantioselectivity). These findings contribute to interpret the chiral behaviour of benzimidazole-sulphoxide anthelmintics.     

Albendazole sulphoxide enantiomeric ratios in plasma and target tissues after intravenous administration of ricobendazole to cattle

The comparative concentration profiles of the (+) and (-) albendazole sulphoxide (ABZSO) enantiomers obtained in plasma and in selected target tissues/fluids after intravenous (i.v.) administration of a racemic formulation of ricobendazole (RBZ) to cattle were characterised. Fourteen Holstein calves received RBZ (racemic solution, 150 mg/mL) by i.v. administration at 7.5 mg/kg. Jugular blood samples were collected over 48 h post-treatment (plasma kinetic trial) and two animals were sacrificed at either 4, 12, 20, 28 or 32 h post-treatment to obtain samples of abomasal/small intestine mucosal tissue, abomasal/small intestine fluids, bile, liver and lung tissue (tissue distribution study). The (-)ABZSO enantiomer was depleted significantly faster from plasma compared with the (+)ABZSO antipode. The plasma AUC for (+)ABZSO (38.3 microg. h/mL) was significantly higher (P < 0.05) compared with that obtained for (-)ABZSO (20.5 microg. h/mL). The (+)ABZSO enantiomer was the predominant antipode measured in bile, abomasal fluid and abomasal mucosa. For instance, at 12 h post-treatment the (+)/(-) concentration ratios were: 12.9 (plasma), 1.62 (abomasal mucosa), 13.0 (abomasal fluid), 2.92 (intestinal mucosa), 9.87 (intestinal fluid) and 21.5 (bile). No marked differences between the concentration profiles of both enantiomers were observed in the liver tissue. Albendazole (ABZ) was recovered from the liver, lung and gastrointestinal (GI) mucosal tissues of RBZ-treated calves up to 32 h post-treatment, probably produced by a GI microflora-mediated sulphoreduction of RBZ. An enantioselective kinetic behaviour may account both for the faster depletion of the (-) enantiomer and for the higher availabilities of the (+) antipode observed in plasma and in most of the tissues/fluids investigated. The simultaneous evaluation of the plasma kinetics and tissue concentration profiles of both enantiomeric forms reported here, may help to interpret the relationship between chiral behaviour and pharmacological action for sulphoxide derivatives of benzimidazole (BZD) methylcarbamate anthelmintics.     

Comparative plasma disposition of fenbendazole, oxfendazole and albendazole in dogs

The plasma disposition of fenbendazole (FBZ), oxfendazole (OFZ) and albendazole (ABZ); and the enantiospecific disposition of OFZ, and ABZSO produced were investigated following an oral administration (50 mg/kg) in dogs. Blood samples were collected from 1 to 120 h post-administration. The plasma samples were analysed by high performance liquid chromatography (HPLC). The plasma concentration of FBZ, OFZ, ABZ and their metabolites were significantly different from each other and depended on the drug administered. The sulphone metabolite (FBZSO2) of FBZ was not detected in any plasma samples and the parent molecule ABZ did not reach quantifiable concentrations following FBZ and ABZ administration, respectively. OFZ and its sulphone metabolite attained a significantly higher plasma concentration and remained much longer in plasma compared with FBZ and ABZ and their respective metabolites. The maximum plasma concentrations (Cmax), area under the concentration time curve (AUC) and mean residence time (MRT) of parent OFZ were more than 30, 68 and 2 times those of FBZ, respectively. The same parameters for ABZSO were also significantly greater than those of FBZSO. The ratio for total AUCs of both the parent drug and the metabolites were 1:42:7 for following FBZ, OFZ and ABZ administration, respectively. The enantiomers were never in racemic proportions and (+) enantiomers of both OFZ and ABZSO were predominant in plasma. The AUC of (+) enantiomers of OFZ and ABZSO was, respectively more than three and seven times larger than that of (-) enantiomers of both molecules. It is concluded that the plasma concentration of OFZ was substantially greater compared with FBZ and ABZ. The data on the pharmacokinetic profile of OFZ presented here may contribute to evaluate its potential as an anthelmintic drug for parasite control in dogs.     

Pharmacokinetic behaviour of netobimin and its metabolites in sheep

The pharmacokinetics and the profile of urine excretion of netobimin (NTB) and its metabolites were investigated after its intraruminal (i.r.) and subcutaneous (s.c.) administration to sheep at 20 mg/kg. Plasma and urine concentrations of NTB, albendazole (ABZ), albendazole sulphoxide (ABZSO) and albendazole sulphone (ABZSO2) were measured serially over a 120-h period by HPLC. NTB showed a similar pharmacokinetic profile in both treatments, being detected between 0.5 and 12 h post-treatment, but the tmax was achieved significantly earlier (P less than 0.05) after s.c. treatment. ABZ was detected in plasma only after i.r. treatment, resulting in a low area under the curve (AUC). The peak plasma concentration (Cmax) and AUC for ABZSO and ABZSO2 were significantly higher after i.r. administration of NTB. In both treatments, the ABZSO Cmax was reached earlier than the ABZSO2 Cmax. The ratio of AUC ABZSO2:ABZSO was higher following s.c. administration (1.33) than following i.r. administration (0.35). The percentages of total dose excreted in the urine as NTB, ABZ, ABZSO and ABZSO2 were 17.05 (i.r.) and 8.16 (s.c.). There was a less efficient conversion of NTB into ABZ metabolites after s.c. administration. The detection of ABZ in plasma and the high ABZSO AUC obtained after i.r. treatment may be of major importance for anthelmintic efficacy.     

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 (ABZSO₂) were detected in the plasma samples. Maximum plasma concentration of ABZSO (0.53 ± 0.14 μg/ml) and ABZSO₂ (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.     

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 (ABZSO₂) metabolites were detected in the plasma samples. Maximum plasma concentrations (C<_max) of ABZSO (4.1 ± 0.7 μg/ml) and ABZSO₂ (1.1 ± 0.4 μg/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 (μg h)/ml) was significantly higher than that ABZSO₂(26.3± 10.1 (μg h)/ml) (p<0.01). (−)−ABZSO and (+)-ABZSO enantiomers were never in racemate proportions in plasma. The AUC of (+)-ABZSO (87.8±20.3 (μg h)/ml) was almost 6 times larger than that of (−)−ABZSO (15.5 ±5.1 (μg h)/ml) (p < 0.001). Netobimin was not detected, and ABZ was predominant and its AUC was significantly higher than that of ABZSO and ABZSO₂, 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 (μg h)/g) and (+)-ABZSO (187.19 ±63.4 (μg 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.     

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.     

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.     

Methimazole-mediated modulation of netobimin biotransformation in sheep: a pharmacokinetic assessment

The effects of modulation of liver microsomal sulphoxidation on the disposition kinetics of netobimin (NTB) metabolites were investigated in sheep. A zwitterion suspension of NTB was given orally at 7.5 mg/kg to sheep either alone (control treatment) or co-administered with methimazole (MTZ) orally (NTB + MTZ oral treatment) or intra-muscularly (NTB + MTZ i.m.) at 3 mg/kg. Blood samples were taken serially over a 72 h period and plasma was analysed by HPLC for NTB and its major metabolites, i.e. albendazole (ABZ), albendazole sulphoxide (ABZSO) and albendazole sulphone (ABZSO2). Only trace amounts of NTB parent drug and ABZ were detected in the earliest samples after either treatment. There were significant modifications to the disposition kinetics of ABZSO in the presence of MTZ. ABZSO elimination half-life increased from 7.27 h (control treatment) to 14.57 h (NTB + MTZ oral) and to 11.39 h (NTB + MTZ i.m.). ABZSO AUCs were significantly higher (P less than 0.05) for the NTB + MTZ oral treatment (+55%) and for the NTB + MTZ i.m. treatment (+61%), compared with the NTB alone treatment. The mean residence times for ABZSO were 12.66 +/- 0.68 h (control treatment), 18.85 +/- 2.35 h (NTB + MTZ oral) and 17.02 +/- 0.90 h (NTB + MTZ i.m.). There were no major changes in the overall pharmacokinetics of ABZSO2 for the concomitant MTZ treatments. However, delayed appearance of this metabolite in the plasma resulted in longer ABZSO2 lag times and a delayed Tmax for treatments with MTZ.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

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)     

Pharmacokinetics of ricobendazole in calves

The pharmacokinetics of ricobendazole (RBZ) and its major metabolite albendazole sulphone (ABZSO2) were studied in six calves, after administration of RBZ (7.5 mg/kg), using a 10% experimental solution by the intravenous (i.v.) route, a 10% commercial solution by the subcutaneous (s.c.) route, and a 10% experimental suspension by the intraruminal (i.r.) route. Blood samples were drawn during a 60-h period. Plasma drug and metabolite concentrations were determined by HPLC. The pharmacokinetic evaluation in each case was prepared by weighted least-squares nonlinear regression analysis. Ricobendazole i.v. data were best fitted by a two-compartment model. The best pharmacokinetic exponents and coefficients were estimated, and the pharmacokinetic variables for RBZ and ABZSO2 were calculated from them. Similar patterns of plasma disposition were found for RBZ after i.r. and s.c. administration, suggesting delayed release from the s.c. site resembling the slow release of the drug from the rumen.     

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.     

Stereospecific pharmacodynamics and pharmacokinetics of carprofen in the dog

The non-steroidal anti-inflammatory drug (NSAID) carprofen (CPF) contains single chiral centre. It was administered orally to Beagle dogs as a racemate (rac-CPF) at a dose of 4 mg per kg body weight and as individual (-)(R) and (+)(S) enantiomers at 2 mg per kg body weight. Each of the enantiomers achieved similar plasma bioavailability following administration as the race-mate as they did following their separate administration. Only the administered enantiomers were detectable when the drug was given in the (-)(R) or (+) (S) form, indicating that chiral inversion did not occur in either direction. Higher plasma concentrations of the (-)(R) (C_max 18 μg/ml, AUC_0–24 118 μg h/ml) than the (+)(S) (C_max 14 μg/ml, AUC_0–24 67 μg h/ml) enantiomer were achieved following administration of the racemate. Both enantiomers distributed into peripheral subcutaneous tissue cage fluids, but C_max and AUC values were lower for both transudate (non-stimulated tissue cage fluid) and exudate (induced by the intracaveal administration of the irritant carrageenan) than for plasma. Drug concentrations in transudate and exudate were similar, as indicated by C_max and AUC values, although CPF penetrated more rapidly into exudate than into transudate. Neither rac-CPF nor either enantiomer inhibited thromboxane B₂ (T × B2) generation by platelets in clotting blood (serum T × B₂, or prostaglandin E₂, (PGE,) and 12-hydroxyeicosatetraenoic acid (1 2-HETE) synthesis in inflammatory exudate. Since other studies have shown that rac-CPF at the 4 mg/kg dose rate possesses analgesic and anti-inflammatory effects in the dog, it is concluded that the principal mode of action of the drug must be by mechanisms other than cyclooxygenase or 12-lipoxygenase inhibition.     

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.     

Enantiospecific pharmacokinetics of ketoprofen in plasma and synovial fluid of horses with acute synovitis

Pharmacokinetic parameters were established for enantiomers of the nonsteroidal anti-inflammatory drug (NSAID) ketoprofen (KTP) administered as the racemic mixture at a dose of 2.2 mg/kg and as separate enantiomers, each at a dose of 1.1 mg/kg to a group of six horses (five mares and one gelding). A four-period cross-over study in a LPS-induced model of acute synovitis was used. After administration of the racemic mixture S(+)KTP was the predominant enantiomer in plasma as well as in synovial fluid. Unidirectional inversion of R(-) to S(+)KTP was demonstrated but the inversion was less marked than previously reported. It is suggested that this reduction could be because of the influence of the inflammatory reaction on hepatic metabolism. The disposition of KTP enantiomers after administration of the racemic mixture was similar to those observed after administration of S(+) and R(-)KTP. The S(+) and R(-)KTP concentrations in synovial fluid were low and short lasting. After administration of R(-)KTP significant concentrations of the optical antipode were detected in synovial fluid.     

Liver microsomal biotransformation of albendazole in deer, cattle, sheep and pig and some related wild breeds

Albendazole (ABZ) biotransformation was studied in vitro in liver microsomes of adult noncastrated male farm animals (ram, buck, bull and boar), castrated adult males (wether, billy and hog), and free living males (fallow buck, red deer stag, mouflon ram, roe buck and wild boar). Liver microsomal fractions were incubated with either ABZ or racemic albendazole sulphoxide (ABZSO). ABZ was extensively metabolized to the (+) and (-) enantiomers of ABZSO, whereas ABZSO underwent a slow oxidation to albendazole sulphone (ABZSO2) in all species. In all species both ABZSO enantiomers were detected. The chiral ratio, (+)-ABZSO/(-)-ABZSO, was greater than one in farm animals, mouflon and wild boar, and less than one in three species of deer. For total ABZ sulphoxidation, deer like species had lower values compared to the other species. Mouflon ram and ram had lower total sulphoxidation rates compared to wethers, as well as ABZ suphoxidation towards (+)-ABZSO. No significant difference occurred comparing ABZSO formation in mouflon ram and ram, but ABZSO2 formation rate in mouflon ram was higher than in rams and wethers. Roe deer stag, fallow buck and red deer stag did not differ in both total-ABZSO and (-)-ABZSO synthesis rates and roe deer stag and fallow buck did not differ in synthesis rates of (+)-ABZSO and ABZSO2. The bull differed from other species in all metabolites studied, except for red deer stag and boar in (-)-ABZSO synthesis rate. The extent of ABZSO sulphonation to ABZSO2 in bull microsomes was more than twice that of other species.