Pharmacokinetic behaviour and anthelmintic efficacy of 1-n-butyl carbamoyl oxfendazole given by intramuscular injection

Oxfendazole (OFZ) was chemically modified to 1-n-butyl carbamoyl OFZ (C₄-OFZ) in an attempt to improve the solubility of OFZ and enable it to be administered by injection. After intramuscular injection to sheep and cattle, C₄-OFZ was metabolised to OFZ which resulted in higher plasma OFZ concentrations that persisted for a considerably longer period than those observed following administration of OFZ orally. The anthelmintic efficacy of injected C₄-OFZ was tested, in sheep, against strains ofTrichostrongylus colubriformis,Haemonchus contortus andOstertagia circumcincta, which were highly resistant to benzimidazoles. In all cases, the C₄-OFZ treatment showed a significant improvement in efficacy over the conventional oral OFZ drench.     

Disposition of oxfendazole in goats and efficacy compared with sheep

The disposition of intraruminally administered oxfendazole (OFZ) in goats was studied at 5, 10 and 20 mg kg-1. The area under the plasma concentration with time curve (AUC) increased with increasing dose but at a declining rate. AUC was lower after intra-abomasal compared with intraruminal administration. OFZ was less effective against drug resistant Trichostrongylus colubriformis in goats than in sheep but was of similar efficacy against drug resistant Haemonchus contortus in both host species. In the same experiment peak plasma levels of OFZ in goats were about half those in sheep given the same dose. Of 70 goats tested in the field, total rumen bypass occurred in 12 per cent and partial bypass in 67 per cent. Lower systemic availability due to bypass would be expected to reduce further anthelmintic efficacy in goats. From the results of these experiments a dose rate of 10 mg kg-1 is recommended for goats. When given at this rate as a divided dose at 12 hourly intervals over 24 hours, OFZ was significantly more effective than a single dose in reducing egg counts.     

Efficacy of a single high oxfendazole dose against gastrointestinal nematodes in naturally infected pigs

The goal of the current experiment was to assess the clinical efficacy of oxfendazole (OFZ) administered as a single oral dose (30 mg/kg) to pigs naturally parasitized with Ascaris suum, Oesophagostomum spp., Metastrongylus spp. and Trichuris suis. Thirty-six local ecotype piglets were divided into three independent experiments, named I, II and III (n = 12 each), respectively. Each experiment involved two different groups (n = 6): Untreated Control and OFZ treated. Animals were naturally parasitized with A. suum (Experiments I, II and III), Oesophagostomum spp. (Experiments I and II), T. suis (Experiments II and III) and Metastrongylus spp. (Experiment I). Pigs in the treated group received OFZ (Synanthic^®, Merial Ltd., 9.06% suspension) orally at 30 mg/kg dose. At five (5) days post-treatment, animals were sacrificed and the clinical efficacy of the OFZ treatment was established following the currently available WAAVP guidelines for a controlled efficacy test. None of the animals involved in this experiment showed any adverse events during the study. OFZ treatment given as a single 30 mg/kg oral dose showed a 100% efficacy against all the nematode parasites present in the three experiments. In conclusion, under the current experimental conditions, OFZ orally administered to naturally parasitized piglets at a single dose of 30 mg/kg was safe and highly efficacious (100%) against adult stages of A. suum, Oesophagostomum spp., T. suis and Metastrongylus spp.     

Failure of a single treatment with ivermectin to control sheep scab (Psoroptes ovis) on artificially infested sheep

Ivermectin at 200 micrograms/kg bodyweight given either as a single subcutaneous injection or as an oral drench failed to eradicate Psoroptes ovis from artificially infested sheep. The oral drench reduced the mite populations by 43 per cent within 24 hours but no further significant decline was recorded over 38 days. The subcutaneous injection reduced the mite populations by 90 per cent after 10 days but live P ovis were present on all the treated animals 84 days after treatment. The efficacy of treatment was less the higher the initial mite burden. The injection had no effect on clinical sheep scab, and the disease continued to progress despite the mite mortality.     

Pharmacokinetics of oxfendazole in goats: a comparison with sheep

In goats, there was a linear correlation of area under the plasma concentration-time curve (AUC) with dose in the range 0-20 mg/kg as single dosages of oxfendazole (OFZ). The bioavailability of OFZ after oral administration was lower in goats than in sheep. The repetition of three administrations at 24 h intervals produced significant increase in the AUC in comparison with a single administration equivalent to the total dosage (1 X 5.0 and 3 X 1.7 mg/kg). Infection with O. circumcincta produced a 33% decrease in the bioavailability of OFZ.     

Plasma achiral and chiral pharmacokinetic behaviour of intravenous oxfendazole co-administered with piperonyl butoxide in sheep

Co-administration of piperonyl butoxide (PB) potentiates fenbendazole (FBZ) in small ruminants. The resultant increase in bioavailability of FBZ and its metabolite oxfendazole (OFZ) has important implications for the efficacy of these drugs against benzimidazole (BZD)-resistant strains of Teladorsagia circumcincta. This study evaluated the racemic (achiral) and enantiomeric (chiral) plasma disposition kinetics of OFZ and its metabolites after the co-administration of PB and OFZ in sheep. Six 6-8-month-old, parasite-free, female Dorset sheep (30-40 kg) were used in a two-phase crossover experiment. In phase I, three sheep received 30 mg/kg PB orally, followed by a single intravenous (i.v.) injection of OFZ at 5 mg/kg. The other three animals were treated similarly except that 5 mL of water replaced PB. In phase 2, treatments for the two groups were reversed and were given 14 days after the initiation of phase I. Three analytes OFZ, FBZ and fenbendazole sulphone (FBZSO(2)) were recovered in plasma up to 48 h post-treatment in both experimental groups. Achiral and chiral pharmacokinetic (PK) profiles for OFZ, after the co-administration of PB, were characterized by a significantly greater area under the concentration--time curve (AUC) and a longer mean residence time (MRT). Chiral OFZ distribution ratios were comparable in both treatment groups. Piperonyl butoxide treatment markedly influenced the plasma PK profiles for FBZ and FBZSO(2) following OFZ administration. Production of FBZ was enhanced as reflected by increased (> 60%) AUC, delayed T(max) and a significantly delayed (> 45%) elimination (t(1/2)(el)). Although AUC values for FBZSO(2) were not significantly different between groups, this metabolite was depleted more slowly from plasma (t(1/2)(el) > 60% and MRT > 42%) following PB treatment. This study demonstrated that PB co-administration is associated with an inhibition of OFZ biotransformation, as evidenced by the significantly higher plasma concentrations of OFZ and FBZ, and this could have important implications in terms of anti-parasite therapy against BZD-resistant parasite strains.     

Efficacy of the avermectins against filarial parasites: A short review

The avermectins are macrocyclic lactones produced byStreptomyces avermitilis. One of them has been chemically modified and given the non-proprietary name invermectin. The compounds have shown efficacy against various stages of filarial parasites. With respect to pre-adult stages in the mammalian host, activity has been observed againstDirofilaria immitis in ferrets and dogs, andDipetalonema viteae andLitomosoides carinii in jirds (Meriones); but activity has not been observed against the developing stages ofBrugia spp. in jirds orOnchocerca spp. in cattle. The compounds have not shown activity against adult filarial worms, except in the case ofSetaria equina in horses and possiblyDipetalonema viteae in jirds. With respect to the first stage larva (microfilaria) in the mammalian host, efficacy has been observed againstDirofilaria immitis in dogs,Brugia malayi in multimammate rats (Mastomys),Dipetalonema viteae andLitomosoides carinii in jirds andOnchocerca spp. in horses and cattle; but activity has not been observed against microfilariae ofBrugia pahangi in jirds or cats. Efficacy against filarial parasites has been observed following oral or parenteral administration of drug, sometimes at extremely low dosage. For example, a single oral dosage of 0.05 mg/kg was highly active against the third and fourth larval stages and microfilariae ofD. immitis in dogs.     

Pharmacokinetic profile and tissue distribution of monensin in broiler chickens

1. The pharmacokinetics of monensin, including half‐life, apparent volume of distribution, total body clearance, systemic bio‐availability and tissue residues were determined in broiler chickens. The drug was given by intracrop and intravenous routes in a single dose of 40 mg/kg body weight.

2. Following intravenous injection the kinetic disposition of monensin followed a two compartments open model with absorption half life of 0.59 h, volume of distribution of 4.11 I/kg and total body clearance of 28.36 ml/kg/min. The highest serum concentrations of monensin were reached 0.5 h after intracrop dosage with an absorption half‐life of 0.27 h and an elimination half life of 2.11 h. The systemic bioavailability was 65.1% after intracorp administration. Serum protein‐binding tendency of monensin calculated in vitro was 22.8%.

3. Monensin concentrations in the serum and tissues of chickens after a single intracrop dose of pure monensin (40 mg/kg body weight) were higher than those after feeding a supplemented monensin pre‐mix (120 mg/kg) for 2 weeks. Monensin residues were detected in tested body tissues, collected 2, 4, 6 and 8 h after oral administration. The highest conentration was found in the liver. In addition, monensin residues were detected only in liver, kidney and fat 24 h after the last oral dose. No monensin residues could be detected in tissues after 48 h, except in liver which cleared completely by 72 h.     

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.     

Pharmacokinetics and bioavailability of 2-mercaptopropionylglycine administered intravenously and orally in dogs

The pharmacokinetic disposition of 2-mercaptopropionylglycine (2-MPG) given as a single intravenous injection and/or as a single oral dose was studied in 9 normal and 13 cystinuric dogs. After intravenous injection of approximately 10 or 20 mg/kg body weight the pharmacokinetics were best described by a three-exponential function. The first phase involved a distribution process apparently including establishment of drug-plasma protein and drug-tissue binding. The second phase involved rapid renal elimination and 60% of the drug was excreted within 3 h of administration. There was also a slow terminal third phase with a long half-life after both intravenous (t1/2 = 23 h) and oral (t1/2 = 22 h) administration. No dose dependency was observed. A deep pool of reversibly tissue-bound 2-MPG was indicated by a Vss of 3.3 +/- 0.9 l/kg body weight and the long terminal elimination phase. Total clearance was estimated as 4.1 +/- 0.9 ml/min/kg body weight. 2-MPG was eliminated mainly by renal excretion, but there was a difference in recovery of dose between normal and cystinuric dogs. During the first 24 h after intravenous and oral administration, 69% and 54%, respectively, of the drug was recovered in the urine of normal dogs. The corresponding figures in cystinuric dogs were 44% and 29%, respectively. The absolute bioavailability (FAUC) was 88 +/- 20% in normal dogs.     

Changes to oxfendazole chiral kinetics and anthelmintic efficacy induced by piperonyl butoxide in horses

REASONS FOR PERFORMING THE STUDY: The study of novel pharmacological strategies to control parasitism in horses is required since many parasite species have developed resistance to anthelmintic drugs. OBJECTIVES: To evaluate the effects of piperonyl butoxide (PB) (a metabolic inhibitor) on the plasma availability and enantiomeric behaviour of oxfendazole (OFZ) given orally to horses, and to compare the clinical efficacy of OFZ given either alone or co-administered with PB in naturally parasitised horses. METHODS: Fifteen naturally parasitised crossbred male ponies were allocated into 3 groups (n = 5) and treated orally as follows: Group I (control) received distilled water as placebo; Group II was dosed with OFZ (10 mg/kg bwt); and Group III was treated with OFZ (10 mg/kg bwt) co-administered with PB (63 mg/kg bwt). Jugular blood samples were obtained over 120 h post treatment. Three weeks after treatments, all experimental horses were subjected to euthanasia. RESULTS: The observed maximum plasma concentration (Cmax) and area under the concentration vs. time curve (AUC) values for OFZ increased 3- and 5-fold, respectively, in the presence of PB. The plasma concentration profiles of fenbendazole (FBZ), a metabolite generated from OFZ, were significantly lower after the treatment with OFZ alone (AUC = 0.8 microg x h/ml) compared to those obtained after the OFZ + PB treatment (AUC = 2.7 microg x h/ml). The enhanced pharmacokinetic profiles correlated with increased anthelmintic efficacy. The combination OFZ + PB showed 100% efficacy against mature nematode parasites. The efficacy against cyathostome L3 larvae increased from 94% (Group II) to 98.7% (Group III). Consistently, the number of L4 larvae recovered from OFZ + PB treated horses (Group III) (n = 146) was significantly lower (P<0.05) than that recovered from Group II (n = 1397). CONCLUSIONS: The use of PB as a metabolic inhibitor may be useful to enhance OFZ activity against mature and migrating larvae of different parasite species in horses. POTENTIAL RELEVANCE: Metabolic inhibitors may be used to enhance the activity of benzimidazole anthelmintics and extend the effective lifespan of benzimidazole drugs in the face of increasing resistance.     

Pharmacokinetics of benzydamine in dairy cows following intravenous or intramuscular administration

Five lactating cows were given benzydamine hydrochloride by rapid intravenous (0.45 mg/kg) and by intramuscular (0.45 and 1.2 mg/kg) injection in a crossover design. The bioavailability, pharmacokinetic parameters and excretion in milk of benzydamine were evaluated. After intravenous administration, the disposition kinetics of benzydamine was best described using a two-compartment open model. Drug disposition and elimination were fast (t _1/2: 11.13±3.76 min;t _1/2: 71.98±24.75 min; MRT 70.69±11.97 min). Benzydamine was widely distributed in the body fluids and tissues (V _d(area): 3.549±1.301 L/kg) and characterized by a high value for body clearance (33.00±5.54 ml/kg per min). After intramuscular administration the serum concentration-time curves fitted a one-compartment open model. Following a dose of 0.45 mg/kg, theC _max value was 38.13±4.2 ng/ml at at _max of 67.13±4.00 min; MAT and MRT were 207.33±22.64 min and 278.01±12.22 min, respectively. Benzydamine bioavailability was very high (92.07%±7.08%). An increased intramuscular dose (1.2 mg/kg) resulted in longer serum persistence (MRT 420.34±86.39 min) of the drug, which was also detectable in milk samples collected from both the first and second milking after treatment.Abbreviations HPLC high-pressure liquid chromatography - IC50 concentration to inhibit the activity of an organism by 50% - IM intramuscular(ly) - IV intravenous(ly) - NSAID non-steroidal antiinflammatory drugs - pK _a negative logarithm of the ionization constant (K _a) of a drug; other abbreviations are listed in footnotes to tables     

Resistance to a triple combination of broad-spectrum anthelmintics in naturally-acquired Ostertagia circumcincta infections in sheep

AIM: To measure the efficacy of two macrocyclic lactone-levamisole-benzimidazole combination drenches against naturally-acquired abomasal nematode infections on a sheep farm in the North Island, New Zealand. METHODS: Eighteen lambs carrying naturally-acquired worm burdens were removed from pasture and randomly allocated to one of three equal-sized groups, consisting of an untreated control group and two treatment groups. One treatment group was given a single oral dose of a triple-combination anthelmintic administered at the manufacturer's recommended dose rate of 0.2 mg/kg ivermectin, 7.5 mg/kg levamisole and 5.0 mg/kg albendazole. The other treatment group received a similar dose of another triple-combination drench consisting of 0.2 mg/kg abamectin, 8.0 mg/kg levamisole and 4.5 mg/kg oxfendazole. Worm counts were carried out post mortem on the abomasa of all animals in all groups, 10 days after treatment. RESULTS: While the abamectin-levamisole-oxfendazole combination was highly effective against all three abomasal nematode species present, the ivermectin-levamisole-albendazole combination was not. In the latter instance, a reduction of only 78% was achieved against infections of Ostertagia (=Teladorsagia) circumcincta. CONCLUSIONS: These results provide evidence of resistance to an ivermectin-levamisole-albendazole combination drench by O. circumcincta. CLINICAL RELEVANCE: Besides representing the first confirmed report of resistance to a combination drench consisting of three broad-spectrum anthelmintics, the present results provide further evidence of the continuing escalation of multiple anthelmintic resistance in sheep nematodes in New Zealand.     

Pharmacokinetics of Pefloxacin in Goats after Intravenous or Oral Administration

The plasma concentrations and pharmacokinetics of the fluoroquinolone antimicrobial agent pefloxacin, following the administration of a single intravenous (10 mg/kg) or oral (20 mg/kg) dose, were investigated in healthy female goats. The antimicrobial activity in plasma was measured at predetermined times after drug administration by an agar well diffusion microbiological assay, using Escherichia coli (ATCC 25922) as the test organism. Concentrations of the drug 0.25 g/ml were maintained in plasma for up to 6 and 10 h after intravenous (IV) or oral administration of pefloxacin, respectively. The concentration–time data for pefloxacin in plasma after IV or oral administration conformed to two- and one-compartment open models, respectively. Plasma pefloxacin concentrations decreased rapidly during the initial phase after IV injection, with a distribution half-life (t _1/2 ) of 0.10±0.01 h. The terminal phase had a half-life (t _1/2 ) of 1.12±0.21 h. The volume of distribution at steady state (V _dss), mean residence time (MRT) and total systemic clearance (Cl_B) of pefloxacin were 1.08±0.09 L/kg, 1.39±0.23 h and 821±88 (ml/h)/kg, respectively. Following oral administration of pefloxacin, the maximum concentration in the plasma (C _max) was 2.22±0.48 g/ml and the interval from administration until maximum concentration (t _max) was 2.3±0.7 h. The absorption half-life (t _{1/2 ka}), mean absorption time (MAT) and elimination half-life of pefloxacin were 0.82±0.40, 4.2±1.0 and 2.91±0.50 h, respectively. The oral bioavailability of pefloxacin was 42%±5.8%. On the basis of the pharmacokinetic data, a dosage regimen of 20 mg/kg, IV at 8 h intervals or orally twice daily, is suggested for treating infections caused by drug-sensitive pathogens in goats.     

The relative plasma availabilities of ivermectin in reindeer (Rangifer tarandus tarandus) following subcutaneous and two different oral formulation applications

Background

Overwintering (breeding) reindeer (Rangifer tarandus tarandus) are commonly treated with ivermectin against parasitic infestations once yearly in autumn-winter roundups. The only preparations registered to reindeer are those for subcutaneous injection. However, also oral extra-label ivermectin administration is used. Twenty-six, 8-month-old reindeer calves were randomly allocated into three groups. Group 1 (n = 9) received oral ivermectin mixture (Ivomec® vet mixt. 0.8 mg/ml, oral ovine liquid drench formulation), Group 2 (n = 9) oral ivermectin paste (Ivomec® vet 18.7 mg/g equine paste), and Group 3 (n = 8) subcutaneous injection of ivermectin (Ivomec® 10 mg/ml vet inj.), each group at a dose of 200 μg/kg body weight. Blood samples were collected at treatment and at days 1, 2, 3, 6, 9 and 16 post treatment. Plasma concentrations of ivermectin were determined by high-pressure liquid chromatography (HPLC) with fluorescence detection.

Results

The peak plasma concentration (C_max) was reached by 2 days after each treatment. The C_max and Area Under Curve (AUC) differed significantly between the groups: C_max was 30.2 ± 3.9, 14.9 ± 5.7 and 63.1 ± 13.1 ng/ml, and AUC_∞ was 2881 ± 462, 1299 ± 342 and 6718 ± 1620 ng*h/ml for groups 1, 2 and 3, respectively (mean ± standard deviation).

Conclusions

The differences in plasma concentrations of ivermectin are concomitant with earlier observed differences in antiparasitic efficacy, which discounts the use of the equine paste in reindeer in favour of the oral ovine liquid drench formulation, or preferably, the reindeer-registered subcutaneous injection formulation.     

Efficacy of moxidectin 1% injectable and 0.2% oral drench against natural infection by Dictyocaulus filaria in sheep

Two separate trials (I and II) with 34 and 32 Churra ewes, respectively, and distributed into two groups, have been carried out to evaluate the efficacy of two different formulations of moxidectin at a dose rate of 0.2mg/kg body weight (b.w.) against natural infection by Dictyocaulus filaria in sheep. Trial I was designed to evaluate a 1% moxidectin injectable formulation, whereas in trial II a 0.2% moxidectin oral drench formulation was used. The efficacy was measured on the basis of the reduction of the faecal larval counts and of adult worm recoveries at slaughter.In each trial, a group of animals was treated on day 0 with moxidectin 1% injectable or moxidectin 0.2% oral drench and the other group acted as untreated control.When the faecal larval counts was compared within the treated groups, the efficacy was over 95% until day +13, and 100% at the remainder of the sampling dates after the application of injectable moxidectin, whereas in trial II, the larvae per gram (lpg) of faeces increased until the first sampling time post treatment (p.t.), day +6, and zero counts were recorded for all animals by the following days. On the basis of adult worm recoveries at necropsy, the efficacy of the treatment was 100% in both trials, however, adult worms were detected at slaughter for all control sheep. These results indicate that moxidectin 1% injectable and moxidectin 0.2% oral drench, administered at 0.2mg/kg b.w., were 100% effective against D. filaria infection in sheep. No adverse reactions to the treatments were observed in the animals.     

Pharmacokinetics, metabolism and renal clearance of flumequine in veal calves

The pharmacokinetics of flumequine was studied in 1-, 5- and 18-week-old veal calves. A two-compartment model was used to fit the plasma concentration-time curve of flumequine after the intravenous injection of 10 mg/kg of a 10% solution. The elimination half-life (t1/2 beta) of the drug ranged from 6 to 7 h. The Vd beta and ClB of 1-week-old calves (1.07 l/kg, 1.78 ml/min/kg) were significantly lower than those of 5-week-old (1.89 l/kg, 3.23 ml/min/kg) and 18-week-old calves (1.57 l/kg, 3.10 ml/min/kg). After the oral administration of 10 mg/kg of a 2% flumequine formulation mixed with milk replacer, the Cmax was highest in 1-week-old (9.27 micrograms/ml) and lowest in 18-week-old calves (4.47 micrograms/ml). The absorption was rapid (Tmax of approximately 3 h) and complete. When flumequine itself and a formulation containing 2% flumequine and 20 X 10(6) iu of colistin sulphate were mixed with milk replacer and administered at the same dose rate, absorption was incomplete and Cmax was lower. The main urinary metabolite of flumequine was the glucuronide conjugate (approximately 40% recovery within 48 h of intravenous injection) and the second most important metabolite was 7-hydroxy-flumequine (approximately 3% recovery within 12 h of intravenous injection). Only 3.2-6.5% was excreted in the urine unchanged. After oral administration a 'first-pass' effect was observed, with a significant increase in the excretion of conjugated drug. For 1-week-old calves it is recommended that the 2% formulation should be administered at a dose rate of 8 mg/kg every 24 h or 4 mg/kg every 12 h; for calves over 6 weeks old, the dose should be increased to 15 mg/kg every 24 h or 7.5 mg/kg every 12 h. The formulation containing colistin sulphate should be administered to 1-week-old calves at a flumequine dose of 12 mg/kg every 24 h or 6 mg/kg every 12 h.     

Some Pharmacokinetic Data for Danofloxacin in Healthy Goats

The pharmacokinetics of danofloxacin was determined in five clinically normal adult female goats after intravenous (IV) or intramuscular (IM) doses of 1.25 mg/kg body weight. Blood and urine samples were collected from each animal at precise time intervals. Serum and urine concentrations were determined using microbiological assay methods and the data were subjected to kinetic analysis. After intravenous injection, the serum concentration–time curves of danofloxacin were characteristic of a two-compartment open model. The drug was rapidly distributed and eliminated with half-lives of 17.71±1.38 min and 81.18±3.70 min, respectively. The drug persisted in the central, highly perfused organs with a K ₁₂/K ₂₁ ratio of 0.67±0.25. The mean volume of distribution at a steady state (V _dss) was 1.42±0.15 L/kg. After intramuscular administration, the serum concentration peaked after 0.58±0.04 h at approximately 0.33±0.01 g/ml. While danofloxacin could be detected in serum for 4 and 6 h, it was recovered in urine for up to 24 and 72 h after IV and IM administration, respectively. The systemic bioavailability after IM injection was 65.70%±10.28% and the serum protein-bound fraction was 13.55±1.78%.     

Tissue concentrations and pharmacokinetics of florfenicol in broiler chickens

1. Florfenicol (30 mg/kg body weight) was administered to broiler chickens via intravenous (iv), intramuscular (im) and oral routes to study its plasma concentrations, kinetic behaviour, systemic bioavailability and tissue content.

2. Following a single iv injection, the kinetic disposition of florfenicol followed a 2‐compartmental open model with an elimination half‐life of 173 min, total body clearance of 26.9 ml/kg/min and a steady state volume of distribution of 5.11 1/kg.

3. The highest plasma concentrations of florfenicol were 3.82 and 3.20 μg/ml following single im and oral administration, respectively. The systemic bioavailability was 96.6% and 55.3% after im and oral administration. The plasma protein binding of florfenicol was 18.5%.

4. Following its administration, the highest tissue concentrations of the drug were found in the kidney bile, lung, muscle, intestine, heart, liver, spleen and plasma. Low concentrations of the drug were found in brain, bone marrow and fat. No florfenicol residues were detected in tissues and plasma after 72 h except in the bile from where it disappeared after 96 h.     

Comparative pharmacokinetics of orbifloxacin in healthy and Pasteurella multocida infected ducks

1. The pharmacokinetic aspects of orbifloxacin were studied in both healthy and naturally diseased ducks after a single intravenous and intramuscular dose of 5?mg?kg^?1 body weight. The serum concentrations of orbifloxacin following single intravenous and intramuscular injections were higher in diseased than in healthy ducks.

2. The disposition of orbifloxacin after a single intravenous injection was described by a two-compartment open model in both healthy and diseased ducks. Orbifloxacin was distributed and eliminated at a significantly slower rate in diseased than in healthy ducks. The total body clearance (Cl_B) was lower in diseased (0·131?l?kg^?1?h^?1) than healthy ducks (0·191?l?kg^?1?h^?1).

3. Following intramuscular administration of orbifloxacin, the peak serum concentration (C_max) was higher in diseased than in healthy ducks, and this was achieved at a maximum time (t_max) of 1·114 and 0·993?h, respectively. The drug was eliminated at a significant slower rate in diseased ducks (elimination half-life t _{0·5( el )?}=?5·07?h) than in healthy ducks (elimination half-life t _{0·5( el )?}=?4·18?h).

4. These results indicate that drug elimination patterns in healthy and diseased ducks are not the same. The pharmacokinetic profile of the drug is altered in diseased ducks due to the increased serum orbifloxacin concentrations compared with clinically healthy ducks. In conclusion, 5?mg?kg^?1 body weight of orbifloxacin administered as a single dose once daily could be useful in the treatment of disease caused by Pasteurella multocida pathogen in ducks.