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.     

Plasma disposition,faecal excretion and in vitro metabolism of oxibendazole following oral administration in horses

Oxibendazole (OBZ) was administered to eight horses at an oral dose of 10 mg kg(-1) bodyweight each. Parent OBZ could only be detected in plasma at the 0.5 and 1.0 hours post administration sampling times and the mean maximum plasma concentration was 0.008 microg ml(-1). Parent OBZ was detected in faeces between 12 and 72 hours after administration and the highest dry faecal concentration was detected at 24 hours. An unidentified metabolite was detected in plasma between 0.5 and 72 hours. The unidentified metabolite in the plasma of treated horses corresponded to the second eluted metabolite in the in vitro study. Metabolism of OBZ to its metabolite in vitro was significantly inhibited by co-incubation with the cytochrome P450 inhibitor piperonyl butoxide. These results indicated that first-pass metabolism decreases OBZ bioavailability in horses. The in vitro metabolism of OBZ was significantly inhibited by piperonyl butoxide and this could be utilised to extend the exposure of nematodes to the parent molecule.     

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.     

Plasma pharmacokinetics and faecal excretion of ivermectin (Eqvalan paste) and doramectin (Dectomax, 1%) following oral administration in donkeys

Ivermectin (IVM- Eqvalan paste, 1.87%) and doramectin (DRM-Dectomax 1%) were each administered orally to donkeys at 200 microgkg(-1) bodyweight. Blood and faecal samples were collected at predetermined times over 30 days and plasma pharmacokinetics and faecal excretion determined. Maximum plasma concentrations (C(max)) of IVM (23.6 ngml(-1)) and DRM (33.9 ngml(-1)) were obtained at (t(max)) 19.2 and 24h, respectively. The area under the concentration curve (AUC) of DRM (228.9 ngdayml(-1)) was significantly larger than that of IVM (119.3 ngdayml(-1)) and mean residence time (MRT) was 6.5 days for IVM and 9.1days for DRM. The highest (dry weight) faecal concentrations (9.33 microgg(-1) - IVM, 12.12 microgg(-1) - DRM) were detected at 55.9 and 48.0 h, respectively and each compound was detected (0.05 microgg(-1)) in faeces between 11h and 9 days following oral administration in donkeys.     

Plasma disposition and faecal excretion of eprinomectin following topical and subcutaneous administration in non-lactating dairy cattle

AIMS: To investigate the plasma disposition and faecal excretion of eprinomectin (EPM) in non-lactating dairy cattle following topical and S/C administration.

METHODS: Holstein dairy cows, 3.5–5 years-old, were selected 20–25 days after being dried off and were randomly allocated to receive EPM either topically (n=5) or S/C (n=5) at dose rates of 0.5 and 0.2?mg/kg bodyweight, respectively. Heparinised blood and faecal samples were collected at various times between 1 hour and 30 days after treatment, and were analysed for concentrations of EPM using high performance liquid chromatography with a fluorescence detector.

RESULTS: The maximum concentration of EPM in plasma (C_max) and the time to reach C_max were both greater after S/C administration (59.70 (SD 12.90) ng/mL and 1.30 (SD 0.27) days, respectively) than after topical administration (20.73 (SD 4.04) ng/mL and 4.40 (SD 0.89) days, respectively) (p<0.001). In addition, S/C administration resulted in greater plasma availability (area under the curve; AUC), and a shorter terminal half-life and mean residence time (295.9 (SD 61.47) ng.day/mL; 2.95 (SD 0.74) days and 4.69 (SD 1.01) days, respectively) compared with topical administration (168.2 (SD15.67) ng.day/mL; 4.63 (SD 0.32) days, and 8.23 (SD 0.57) days, respectively) (p<0.01). EPM was detected in faeces between 0.80 (SD 0.45) and 13.6 (SD 4.16) days following S/C administration, and between 1 (SD 0.5) and 20.0 (SD 3.54) days following topical administration. Subcutaneous administration resulted in greater faecal excretion than topical administration, expressed as AUC adjusted for dose (1188.9 (SD 491.64) vs. 311.5 (SD 46.90) ng.day/g; p<0.05). Maximum concentration in faeces was also higher following S/C than topical administration (223.0 (SD 63.96) vs. 99.47 (SD 43.24) ng/g; p<0.01).

CONCLUSIONS: Subcutaneous administration of EPM generated higher plasma concentrations and greater plasma availability compared with topical administration in non-lactating cattle. Although the S/C route provides higher faecal concentrations, the longer faecal persistence of EPM following topical administration may result in more persistent efficacy preventing establishment of incoming nematode larvae in cattle.     

Plasma pharmacokinetics and faecal excretion of ivermectin, doramectin and moxidectin following oral administration in horses

The present study was carried out to investigate whether the pharmacokinetics of avermectins or a milbemycin could explain their known or predicted efficacy in the horse. The avermectins, ivermectin (IVM) and doramectin (DRM), and the milbemycin, moxidectin (MXD), were each administered orally to horses at 200 microg/kg bwt. Blood and faecal samples were collected at predetermined times over 80 days (197 days for MXD) and 30 days, respectively, and plasma pharmacokinetics and faecal excretion determined. Maximum plasma concentrations (Cmax) (IVM: 21.4 ng/ml; DRM: 21.3 ng/ml; MXD: 30.1 ng/ml) were obtained at (tmax) 7.9 h (IVM), 8 h (DRM) and 7.9 h (MXD). The area under the concentration time curve (AUC) of MXD (92.8 ng x day/ml) was significantly larger than that of IVM (46.1 ng x day/ml) but not of DRM (53.3 ng x day/ml) and mean residence time of MXD (17.5 days) was significantly longer than that of either avermectin, while that of DRM (3 days) was significantly longer than that of IVM (2:3 days). The highest (dry weight) faecal concentrations (IVM: 19.5 microg/g; DRM: 20.5 microg/g; MXD: 16.6 microg/g) were detected at 24 h for all molecules and each compound was detected (> or = 0.05 microg/g) in faeces between 8 h and 8 days following administration. The avermectins and milbemycin with longer residence times may have extended prophylactic activity in horses and may be more effective against emerging and maturing cyathostomes during therapy. This will be dependent upon the relative potency of the drugs and should be confirmed in efficacy studies.     

Pharmacokinetics of fenbendazole following intravenous and oral administration to pigs

OBJECTIVE: To determine pharmacokinetics and metabolic patterns of fenbendazole after IV and oral administration to pigs. ANIMALS: 4 mixed-breed female pigs weighing 32 to 45 kg. PROCEDURE: Fenbendazole was administered IV at a dose of 1 mg/kg. One week later, it was administered orally at a dose of 5 mg/kg. Blood samples were collected for up to 72 hours after administration, and plasma concentrations of fenbendazole, oxfendazole, and fenbendazole sulfone were determined by use of high-pressure liquid chromatography. Plasma pharmacokinetics were determined by use of noncompartmental methods. RESULTS: Body clearance of fenbendazole after IV administration was 1.36 L/h/kg, volume of distribution at steady state was 3.35 L/kg, and mean residence time was 2.63 hours. After oral administration, peak plasma concentration of fenbendazole was 0.07 microg/ml, time to peak plasma concentration was 3.75 hours, and mean residence time was 15.15 hours. Bioavailability of fenbendazole was 27.1%. Oxfendazole was the major plasma metabolite, accounting for two-thirds of the total area under the plasma concentration versus time curve after IV and oral administration. Fenbendazole accounted for 8.4% of the total AUC after IV administration and 4.5% after oral administration. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicate that fenbendazole was rapidly eliminated from plasma of pigs. The drug was rapidly absorbed after oral administration, but systemic bioavailability was low.     

Intravenous disposition kinetics, oral and intramuscular bioavailability and urinary excretion of norfloxacin nicotinate in donkeys

An aqueous solution of norfloxacin nicotinate (NFN) was administered to donkeys (Aquus astnus) intravenously (once at 10 mg/kg), intramuscularly and orally (both routes once at 10 and 20 mg/kg, and for 5 days at 20 mg/kg/day). Blood samples were collected at predetermined times after each treatment and urine was sampled after intravenous drug administration. Serum NFN concentrations were determined by microbiological assay. Intravenous injection of NFN over 45–60 s resulted in seizures, profuse sweating and tachycardia. The intravenous half-life (t_1/2β was 209 ± 36 min, the apparent volume of distribution (V_d(area)) was 3.34 ± 0.58 L/kg, the total body clearance (Cl_E) was 1.092 ± 0.123 ± 10^--²mL/min/kg and the renal clearance (C1_R) was 0.411 ± 0.057 ± 10^--²mL/min/kg. Oral bioavailability was rather poor (9.6% and 6.4% for the 10 and 20 mg/kg doses respectively). Multiple oral treatments did not result in any clinical gastrointestinal disturbances. After intramuscular administration (20 mg/kg), serum NFN concentrations > 0.25 μg/mL (necessary to inhibit the majority of gram-negative bacteria isolated from horses) were maintained for 12 h. The intramuscular bioavailability was 31.5% and 18.8% for the 10 and 20 mg/kg doses respectively. After multiple dosing some local swelling was observed at the injection site. About 40% of the intravenous dose was recovered in the urine as parent drug. The results of comprehensive haematological and blood biochemistry tests indicated no abnormal findings except elevation in serum CPK (creatine phosphokinase) values after multiple intramuscular dosing. On the basis of the in vitro-determined minimum inhibitory concentrations of the drug and serum concentrations after multiple dosing, the suggested intramuscular dosage schedules for the treatment of gram-negative bacterial infections in Equidae are 10 mg/kg every 12 h or 20 mg/kg every 24 h.     

Influence on the antithyroid compound methimazole on the plasma disposition of fenbendazole and oxfendazole in sheep

The influence of methimazole on the plasma disposition kinetics of fenbendazole, oxfendazole and their metabolites, was investigated in adult sheep. The two anthelmintics were administered by oral drench at 5 mg kg⁻¹ either alone (control treatments) or together with methimazole given orally at 3 mg kg⁻¹. Blood samples were taken serially for 144 hours. Fenbendazole parent drug and its sulphoxide and sulphone metabolites were the three analytes observed by high performance liquid chromatography ( ) after the administration of both anthelmintics. The disposition of each analyte followed a similar pattern after the administration of the two anthehnintics alone. Oxfendazole was the main component recovered in plasma between four and 120 to 144 hours after the administration of both anthelmintics either with or without methimazole. A modified pattern of disposition, with significantly higher C_max and values for fenbendazole parent drug, and a delayed appearance in plasma with retarded T_max values for the sulphoxide and sulphone metabolites, were the main pharmacokinetic changes observed when the drugs were administered with methimazole.     

Plasma disposition of amikacin and interactions with gastrointestinal microflora in Equidae following intravenous and oral administration

Amikacin was detectable (> 0.02 μg/ml) in plasma for 12 h in horses and donkeys and for 8 h in ponies following intravenous (i.v.) administration at a dose the rate of 6 mg/kg bodyweight The elimination half-life (harmonic mean) of amikacin was 2.8, 1.6 and 1.9 h in horses, ponies and donkeys, respectively, and the mean body clearance was relatively slow (45.2, 82.4 and 58.0 ml/h.kg, respectively). A suitable dosage interval for the i.v. administration of amikacin sulphate to horses, ponies and donkeys, at a dose rate of 6 mg/kg, would be every 8 h in horses, and every 6 h in ponies and donkeys. Following i.v. administration there were no marked alterations in caecal liquor pH, the number of viable bacteria isolated, or the short chain fatty acid (SCFA) concentrations in caecal liquor and faeces. Amikacin was not detected (< 0.02 μg/ml) in plasma following administration by nasogastric tube to ponies with cannu-lated caecal fistulae; however, there were high concentrations of amikacin measured in caecal liquor (maximum 16.2–99.4 μg/ml). Despite the high drug concentrations in caecal liquor, there were only slight alterations in the number of viable bacteria isolated. However, there was a reduction in caecal liquor pH to < 6.6, but few changes in caecal liquor SCFA concentrations. Faecal SCFA concentrations, dry matter content and consistency did not alter markedly.     

The disposition kinetics of albendazole following the administration of single and divided doses to cattle and buffalo

Concentrations of albendazole sulphoxide and its sulphone metabolite in plasma in cattle and buffalo were measured by high-performance liquid chromatography after single and divided intraruminal administration of albendazole at the recommended nematocidal and fasciolicidal dose rates of 7.5 and 15.0 mg/kg body weight, respectively. No significant differences in the plasma concentrations of the metabolites or their pharmacokinetic parameters were observed between cattle or buffalo at either dose rate. Pharmacokinetic analysis and the disposition curve of the metabolites indicated increased uptake of the drug in both cattle and buffalo when the same total amount of the drug was given in divided doses compared to a single dose (p<0.05). The divided dose schedules of administration could possibly be exploited to extend the life of the available benzimidazole anthelmintics.     

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.     

奥芬达唑和阿苯达唑对猪囊尾蚴作用形态学比较观察

观察了奥芬达唑和阿苯达唑对猪体内及体外培养的不同发育阶段囊尾蚴作用的形态学效果.结果表明奥芬达唑具有显著的疗效,优于阿苯达唑,且对未成熟期猪囊尾蚴的杀灭作用优于成熟期.提示奥芬达唑可能成为抗未成熟期猪囊尾蚴及治疗脑囊虫病的有效药物.     

The pharmacokinetics of fenbendazole and oxfendazole in cattle

The pharmacokinetics of fenbendazole and oxfendazole in cattle are described. The pharmacokinetics of oxfendazole were not significantly different when administered orally and by intra-ruminal injection. At a dose rate of 4.5 mg/kg, administered orally, fenbendazole gave rise to mean peak concentrations in plasma of fenbendazole and oxfendazole of 0.11 and 0.13 microgram/ml respectively. Oral administration of oxfendazole, at 4.5 mg/kg body weight, gave rise to plasma peak concentrations of fenbendazole and oxfendazole of 0.10 and 0.20 microgram/ml respectively. Following intra-ruminal administration of oxfendazole, the peak concentrations were 0.11 and 0.18 microgram/ml respectively.