Clorsulon pharmacokinetics in sheep and goats following oral and intravenous administration

Clorsulon was measured in plasma and urine of sheep and goats after administration of a single intravenous (i.v.) and after a single oral dose of 7 mg/kg. A three-compartment model with elimination occurring from the central compartment was determined to best describe the i.v. data, whereas a one-compartment model with a single exponential absorption phase best described the oral plasma data. The bioavailability of orally administered clorsulon was approximately 55% in goats and 60% in sheep. Peak plasma concentrations occurred at 14 h and 15 h after oral administration in goats and sheep, respectively. Absorption from the gastro-intestinal tract effectively prolonged the elimination of clorsulon by increasing the elimination half-life from 17 to 28 h in sheep and from 12 to 23 h in goats for the i.v. and oral routes, respectively. In both goats and sheep, approximately 50% of the i.v. dose was recovered in urine as parent drug at 48 h after administration, whereas 41% and 30% of the dose was recovered after oral administration for goats and sheep, respectively. The elimination rate constant (kel) in goats was nearly twice as large as the value determined in sheep, and the urea under the i.v. plasma curve in goats was only 63% of the value in sheep indicating that goats are more effective in their capacity to eliminate clorsulon than are sheep. These differences in drug disposition between sheep and goats may account for the reduced efficacy of clorsulon reported in goats.     

The effect of niclofolan on desert sheep experimentally infected with immature Fasciola gigantica

Eight desert sheep were each infected orally with 500 metacercariae of Fasciola gigantica and, after 4 weeks, four of the animals were given niclofolan orally at the recommended therapeutic dose rate of 7 mg/kg, the other four remaining as controls. One week later, the animals were slaughtered and the fasciocidal effect of the drug was evaluated on the basis of worm burden, haemogram, some plasma constituents, and gross and histopathological lesions of the liver, as indicators of efficacy. The treatment was found to be ineffective, the degree of infection remaining the same as in the untreated control group. The experiment was repeated using eight infected sheep: four were given the drug orally at a dose rate of 10.5 mg/kg, i.e., 1.5 times the recommended dose; and the same parameters were measured as described above. The drug failed to cure the infected sheep, and caused depression, anorexia and weakness. In a third experiment six sheep were infected as before and three were treated with niclofolan by deep i.m. injection at the recommended therapeutic dose of 2 mg/kg. A week later the animals were killed and examined as before. The drug was effective in treating the infection and produced no untoward effects except for transient signs of pain at the site of injection. It seems possible that the oral dose, unlike the i.m. dose, of niclofolan is not absorbed and/or metabolized sufficiently to prevent elimination of the infection.     

A study of the pharmacokinetics and tissue residues of an oral trimethoprim/sulphadiazine formulation in healthy pigs

Twenty-six healthy female pigs weighing 19.5-33 kg were used in three separate experiments. The animals were fed individually twice a day. Trimethoprim/sulphadiazine (TMP/SDZ) formulation was added to feed in the amount of 6 mg/kg bw (TMP) and 30 mg/kg bw (SDZ). TMP and SDZ concentrations in blood plasma, muscles, liver and kidneys were measured. Pharmacokinetic parameters show that the absorption of TMP from the alimentary tract in pigs is faster than the absorption of SDZ, and the elimination of TMP is slower than that of SDZ. The absorption half-lives were 0.96 (TMP) and 2.24 h (SDZ), whereas elimination half-lives were 5.49 (TMP) and 4.19 h (SDZ). The observed TMP:SDZ ratios in blood plasma after multiple dose administration ranged from 1:11.4 to 1:23.2. One day after administration of the last dose of TMP/SDZ the plasma concentration ratio was 1:15.5, but in muscles, liver and kidneys it was much lower: 1:0.79, 1:0.14 and 1:1.53 respectively. The absolute TMP and SDZ tissue concentrations 1 day after the last multiple dose administration were very low (maximum TMP: 0.29 μg/g in liver; maximum SDZ: 0.23 μg/g in kidneys). Neither drug was detected in any tissue 8 days after the last administration of TMP/SDZ. Based on our results, it was concluded that there is no support for the TMP:SDZ pharmaceutical ratio 1:5 in oral formulations of these compounds for pigs. The administration of oral TMP/SDZ formulations once a day may result in the absolute tissue concentrations of these drugs being too low for antibacterial activity. The withdrawal period for such an oral TMP/SDZ formulation for pigs (according to accepted guidelines in Europe for MRL of TMP < 0.05 mg/kg of tissue) should not be less than 5 days.     

Plasma profiles of ivermectin in horses following oral or intramuscular administration

A study was undertaken in order to evaluate and compare ivermectin's (IVM) plasma disposition kinetic parameters after oral or intramuscular (IM) administration in horses. Ten clinically healthy adult horses, weighing 380-496 kg body weight (BW), were allocated to two experimental groups of five horses. Group I, was treated with an oral paste formulation of IVM at the manufacturer's recommended dose of 0.2 mg/kg BW. Group II, was treated IM with an injectable 1% formulation of IVM at a dose of 0.2 mg/kg BW. Blood samples were collected by jugular puncture at different times between 0.5 h and 75 days post-treatment. After plasma extraction and derivatization, samples were analysed by high-performance liquid chromatography with fluorescence detection. A computerized kinetic analysis was performed, and data were compared using the Wilcoxon signed rank test. The parent molecule was detected in plasma between 30 min and either 20 (oral) or 40 (IM) days post-treatment. Significant differences were found for the time corresponding to peak plasma concentrations (tmax) and for absorption half-life. Peak plasma concentrations (Cmax) of 51.3 +/- 16.1 ng/ml (mean +/- SD) were obtained after oral administration and of 31.4 +/- 6.0 ng/ml for the IM route. The values for area under concentration-time curve were 137.1 +/- 35.9 ng day/ml for the group treated orally, and 303.2 +/- 4.3 ng day/ml for the IM treated group. The mean plasma residence times were 4.2 +/- 0.4 and 8.9 +/- 0.7 days for oral and IM-treated groups, respectively. The results of this study show that the route of administration considerably affects the disposition of IVM. A significant difference in bioavailabilty and half-life of elimination of IVM was observed after IM administration compared with oral administration. A close relationship between pharmacokinetic profiles and the clinical efficacy of IVM was established.     

Bioavailability of levamisole after intramuscular and oral administration in sheep

AIMS: To determine the bioavailability of levamisole in sheep. METHODS: Levamisole was administered to three groups of six Merino sheep orally and intramuscularly at three dose levels of 5, 7.5 and 10 mg/kg. There was a washout period of 1 week between treatments. Blood samples were collected by jugular venepuncture and plasma was separated immediately by centrifugation and stored at 20 degrees C until analysed. The levamisole concentration in plasma was determined by high performance liquid chromatography with a U.V. detection method. Individual plasma levamisole concentration-time data were analysed using the compartmental method. RESULTS: The values obtained for k(a), C(max), t(max) and F show a moderate rate and extent of absorption after oral administration of levamisole while, after intramuscular administration, these values demonstrate a high rate and extent of absorption of levamisole. The intramuscular bioavailability was higher than the oral bioavailability (rate of absorption three-fold faster, extent of absorption 25-33% higher and C(max) two-fold higher). The Friedman test involving dose and route of administration showed that the route of administration affects k(a), C(max), t(max) and F; significant differences were found in these parameters. CLINICAL RELEVANCE: On the basis of these data, the recommended routes for the administration of levamisole in sheep are oral for gastro-intestinal nematodiasis and intramuscular for extragastric nematodiasis.     

Pharmacokinetics of intramuscularly administered pethidine in dogs and the influence of anaesthesia and surgery

The plasma concentration of pethidine was measured after it had been administered intramuscularly to fully conscious dogs, and to dogs in the postoperative period and during general anaesthesia. The absorption of the drug was erratic except in the anaesthetised animals and the plasma concentrations of the drug were also higher in this group. Correlation of plasma concentrations of the drug with its analgesic activity revealed a 'critical' concentration of pethidine of 0.4 micrograms/ml for complete analgesia; useful though not complete analgesia was achieved with concentrations above 0.2 micrograms/ml. These concentrations were maintained for 90 minutes after the administration of the drug at a dose of 2.0 mg/kg and for 120 minutes after a dose of 3.5 mg/kg.     

Pharmacokinetics of Amoxicillin Trihydrate in Desert Sheep and Nubian Goats

The pharmacokinetics of amoxicillin were studied in five Desert sheep and five Nubian goats after intravenous (i.v.) or intramuscular (i.m.) administration of a single dose of 10 mg/kg body weight. Following i.v. injection, the plasma concentration-versus-time data were best described by a two-compartment open model. The kinetic variables were similar in both species except for the volume of the central compartment (V_c), which was larger in sheep (p<0.05). Following i.m. injection, except for the longer half-life time of absorption in goats (p<0.05), there were no significant differences in other pharmacokinetic parameters between sheep and goats. The route of amoxicillin administration had no significant effect on the terminal elimination half-life in either species. The bioavailability of the drug (F) after i.m. administration was high (>0.90) in both species. These results indicate that the pharmacokinetics of amoxicillin did not differ between sheep and goats; furthermore, because of the high availability and short half-life of absorption, the i.m. route gives similar results to the i.v. route. Therefore, identical intramuscular and intravenous dose regimens should be applicable to both species.     

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.     

Dose-dependent systemic exposure of albendazole metabolites in lambs

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

Disposition of flunixin meglumine injectable preparation administered orally to healthy horses

An injectable preparation of flunixin meglumine was administered orally and intravenously at a dose of 1.1 mg/kg to six healthy adult horses in a cross-over design. Flunixin meglumine was detected in plasma within 15 min of administration and peak plasma concentrations were observed 45-60 min after oral administration. Mean bioavailability of the oral drug was 71.9 +/- 26.0%, with an absorption half-life of 0.76 h. The apparent elimination half-life after oral administration was 2.4 h. The injectable preparation of flunixin meglumine is suitable for oral administration to horses.     

Faecal excretion profile of moxidectin and ivermectin after oral administration in horses

A study was undertaken to evaluate and compare faecal excretion of moxidectin and ivermectin in horses after oral administration of commercially available preparations. Ten clinically healthy adult horses, weighing 390-446 kg body weight (b.w.), were allocated to two experimental groups. Group I was treated with an oral gel formulation of moxidectin at the manufacturer's recommended therapeutic dose of 0.4 mg/kg b.w. Group II was treated with an oral paste formulation of ivermectin at the recommended dose of 0.2 mg/kg b.w. Faecal samples were collected at different times between 1 and 75 days post-treatment. After faecal drug extraction and derivatization, samples were analysed by High Performance Liquid Chromatography using fluorescence detection and computerized kinetic analysis.For both drugs the maximum concentration level was reached at 2.5 days post administration. The ivermectin treatment groups' faecal concentrations remained above the detectable level for 40 days (0.6 +/- 0.3 ng/g), whereas the moxidectin treatment group remained above the detectable level for 75 days (4.3 +/- 2.8 ng/g). Ivermectin presented a faster elimination rate than moxidectin, reaching 90% of the total drug excreted in faeces at four days post-treatment, whereas moxidectin reached similar levels at eight days post-treatment. No significant differences were observed for the values of maximum faecal concentration (C(max)) and time of C(max)(T(max)) between both groups of horses, demonstrating similar patterns of drug transference from plasma to the gastrointestinal tract. The values of the area under the faecal concentration time curve were slightly higher in the moxidectin treatment group (7104 +/- 2277 ng.day/g) but were not significantly different from those obtained in the ivermectin treatment group (5642 +/- 1122 ng.day/g). The results demonstrate that although a 100% higher dose level of moxidectin was used, attaining higher plasma concentration levels and more prolonged excretion and gut secretion than ivermectin, the concentration in faeces only represented 44.3+/- 18.0% of the total parental drug administered compared to 74.3 +/- 20.2% for ivermectin. This suggests a higher level of metabolization for moxidectin in the horse.     

Influence of a pig respiratory disease on the pharmacokinetic behaviour of amoxicillin after oral ad libitum administration in medicated feed

The pharmacokinetic properties of amoxicillin in healthy and respiratory-diseased pigs were studied, after ad libitum administration of medicated feed. In addition, amoxicillin dose linearity and drug penetration into respiratory tract tissues were evaluated in diseased animals. The respiratory disease involves porcine reproductive and respiratory syndrome virus and bacterial agents such as Pasteurella multocida, Bordetella bronchiseptica and Streptococcus suis. Typical clinical signs and gross lesions of respiratory disease were observed. The plasma pharmacokinetic analysis was performed by means of a noncompartmental approach. After single intravenous bolus administration of amoxicillin to healthy pigs, the steady-state volume of distribution was 0.61 L/kg, the total plasma clearance was 0.83 L/h/kg and the mean residence time was 0.81 h. After oral bolus administration, the mean absorption time was 1.6 h and the peak plasma concentration (3.09 μg/mL) reached at 1.1 h postadministration. The oral bioavailability was 34%. For oral ad libitum administration, plasma concentration-time profiles were related to the feeding behaviour. Plasma concentrations at steady-state were established between 12 and 120 h. The pharmacokinetic parameters calculated (C(maxss) , C(minss) , C(avss) and AUC(24ss) ) showed significantly lower values in healthy pigs compared to diseased animals. This was in accordance with the significantly higher amoxicillin bioavailability (44.7% vs. 14.1%) and longer absorption period observed in diseased pigs. Amoxicillin dose linearity in diseased animals was established in a dose range of 4-18 mg/kg. On the other hand, tissue distribution ratio in diseased animals was 0.65 for bronchial mucosa, 0.48 for lung tissue and 0.38 for lymph nodes. Our results suggest that the pharmacokinetic properties and disposition of amoxicillin can be influenced by the disease state or by related factors such as changes in the gastrointestinal transit.     

The influence of the rumen on the absorption of drugs: studies using meclofenamic acid administered by various routes to sheep and cattle

As part of a general study of the pharmacokinetics of drugs in the ruminant animal, the absorption and distribution kinetics of meclofenamic acid between the gastro-intestinal tract and plasma of sheep and cattle were investigated. Meclofenamic acid is a non-steroidal anti-inflammatory drug which has been shown to possess anti-anaphylactic activity in cattle (Aitken & Sanford, 1969; 1972; Wells, Eyre & Lumsden, 1973) and sheep (Alexander, Eyre, Head & Sanford, 1970) and although marketed only for the horse in the United Kingdom (Arquel, Warner-Lambert) is known to be used in ruminant animals as an anti-inflammatory drug, for its inhibitory effects on prostaglandin synthesis (Smith G. G. A. 1977, personal communication) and for its anti-pyretic action (Van Miert, Van der Wal-Komproe & Van Duin, 1977). The aims of the study were first to evaluate the contribution of reticular (oesophageal) groove closure in directing orally administered drug directly to the abomasum and to assess the rate of absorption through the ruminal epithelium. Second, since Aitken & Sanford (1975) have described the plasma levels of meclofenamate after administration of sodium meclofenamate to cattle by the oral, intravenous and intra-ruminal routes, it was decided to complement their study and to measure the plasma levels after intra-muscular injection of sodium meclofenamate. This route is more convenient in cattle than the oral and intravenous routes examined by them. Lastly, the biphasic pattern of plasma levels of meclofenamate observed by Aitken & Sanford (1975) following oral administration of sodium meclofenamate to cattle was further examined using weaned and unweaned calves in an attempt to confirm their view that some of the drug is delivered to the abomasum directly, by-passing the rumen, by closure of the reticular groove.     

Diminazene aceturate residues in the tissues of healthy, Trypanosoma congolense and Trypanosoma brucei brucei infected dogs

The tissue distribution and residue profile of diminazene aceturate was investigated in healthy dogs and in dogs infected with Trypanosoma congolense and Trypanosoma brucei brucei. The drug was administered at 3.5 mg/kg i.m. and tissue samples were taken post mortem from the animals at 48, 72, 120, 168 and 240 h after injection. The drug was distributed to various organs and tissues of the body with the highest concentrations occurring in liver and kidney. Higher drug levels were obtained in the tissues of healthy dogs compared with trypanosome infected animals except in the brain. The levels of residues in the healthy animals were significantly different (P less than 0.05) from those of the infected dogs. The drug residues were still detectable in the tissues of the animals 10 days after drug administration.     

Disposition kinetics of doxycycline in chickens naturally infected with Mycoplasma gallisepticum

1. The pharmacokinetic properties of doxycycline were determined in healthy chickens and chickens naturally infected with Mycoplasma gallisepticum after a single intravenous (i.v.) and oral administration of the drug at 20 mg/kg body weight. Tissue residues of the tested drug after an oral dose of 20 mg/kg given twice daily for 5 consecutive days were also estimated in diseased chickens. 2. The plasma concentrations of doxycycline following single i.v. and oral administration were higher in healthy chickens than in diseased ones. Following i.v. injection, the elimination half-life (t1/2beta), distribution half-life and mean residence time (MRT) were longer in healthy chickens than in diseased birds. The values of total body clearance (ClB) and volume of distribution (Vdss) were larger in healthy chickens than in diseased birds. 3. After single oral administration, the absorption half-life (tl/2ab) and the elimination half-life were longer in normal birds than in diseased ones. The maximum plasma concentration of the drug was higher in normal chickens than in diseased ones. 4. Following repeated oral administration, the concentration of doxycycline in all tissues except muscle was higher than the corresponding concentrations in plasma. Concentrations of doxycycline in different tissues were in the following order: kidney > liver > lung > muscle. The drug was detected in liver and kidney in substantial concentrations on d 5 post administration of the last dose whereas, on d 7, its concentration in all tissues was below the lower limit of the sensitivity of the assay method used. Because of the low sensitivity of the microbiological assay method used in this study, a safe withdrawal time for doxycycline in diseased birds could not be estimated for the meanwhile.     

Ketoconazole increases the plasma levels of ivermectin in sheep

The parasiticide ivermectin and the antifungal drug ketoconazole are drugs that interact with P-glycoprotein. We have tested the ability of ketoconazole at a clinical dose to modify the pharmacokinetics of ivermectin in sheep. Lacaune lambs were administered with a single oral dose of ivermectin alone at 0.2mg/kg (n=5) or in combination with a daily oral dose of ketoconazole (10mg/kg) given for 3 days before and 2 days after the ivermectin (n=5). The plasma kinetics of ivermectin and its metabolite were followed over 15 days by HPLC analysis. Co-administration of ketoconazole induced higher plasma concentrations of ivermectin, leading to a substantial increase in the overall exposure of the animals to the drug. Ketoconazole did not reduce the production of the main ivermectin metabolite but it may rather act by inhibiting P-glycoprotein, and thus increasing the absorption of ivermectin. The use of a P-gp reversing agent such as ketoconazole could be useful tool to optimize antiparasitic therapy in the face of the worldwide development of anthelmintic resistance.     

Determination of trimethoprim and sulphadoxine residues in porcine tissues and plasma.

Healthy gilts and market-ready hogs were administered a single intramuscular (IM) injection of Borgal, a commercial formulation of trimethoprim-sulfadoxine (TMP-SDX), once or twice daily. The objectives were to determine if a newly-developed high-performance liquid chromatographic (HPLC) method would be suitable for measuring the residual concentrations of TMP in the plasma of these live animals, and to determine if the administration of this veterinary drug would leave measurable residues in their plasma and tissues at slaughter. Plasma and tissue concentrations of SDX and TMP from these animals were determined over a period of 14 d using thin-layer chromatography/densitometry (TLCD), and the newly-developed HPLC method, respectively. The lowest detectable limit (LDL) for SDX in plasma and tissue was 20 ppb by TLCD. The HPLC method had a LDL of 5 ppb for TMP in plasma and tissue. Both methods were then used to provide baseline data on the absorption and depletion of TMP and SDX from these healthy animals. It was observed that both TMP and SDX were readily absorbed into the blood and tissues, but TMP was eliminated much faster than SDX. No TMP residues were detected in the plasma of any of the gilts at and beyond 21 h after drug administration. Also, no TMP residues were detected in the plasma of any of the market-ready hogs 24 h after drug administration at either the label dose or twice the label dose. Sulfadoxine residues at concentrations above the maximum residue limit (MRL) of 100 ppb were, however, detected in the plasma, muscle, kidney, liver, and injection sites of hogs slaughtered 1 and 3 d after a single IM administration at the label dose. Although SDX residues were still detectable in the lungs, kidney, liver and plasma of some hogs 10 d after administration of the label dose and twice the label dose, these were below the MRL. Postmortem examination revealed necrosis and inflammation at the injection sites, but no visible deposits of the injected drug.     

Metabolite concentrations in plasma following treatment of cattle with five anthelmintics

Plasma concentrations of anthelmintics and their metabolites were determined after cattle were treated at recommended dose rates and routes of administration. Fenbendazole, oxfendazole, febantel, albendazole and thiabendazole were given orally and oxfendazole was also administered with an intraruminal injector. After fenbendazole, oxfendazole and febantel were administered, fenbendazole, oxfendazole and fenbendazole sulphone were all detected in plasma in each case. However, there were marked differences between the three anthelmintics in the peak concentrations and areas under the plasma concentration/time curve (AUC) of these three metabolites. Intraruminal administration of oxfendazole produced higher AUC for fenbendazole and fenbendazole sulphone than did oral administration. Albendazole sulphoxide and sulphone were detected in cattle plasma after albendazole administration but no parent drug was present. These metabolites disappeared more rapidly in cattle than has been reported for sheep. Only 5(6)hydroxythiabendazole was detected in cattle plasma after thiabendazole treatment.     

Ivermectin (3.15%) long-acting formulations in cattle: absorption pattern and pharmacokinetic considerations

Ivermectin (IVM) is a broad-spectrum antiparasitic drug extensively used in veterinary medicine. The composition of the pharmaceutical preparation affects IVM absorption and its systemic availability. After the introduction of the first approved IVM formulation (propylene glycol/glycerol formal 60:40) used at 200 microg/kg, different pharmaceutical modifications have been assayed to extend IVM persistent endectocide activity. Recently, IVM 3.15% long-acting (IVM-LA) preparations to be administered at 630 microg/kg to cattle were introduced into the veterinary pharmaceutical market. The work reported here was designed to evaluate the comparative IVM absorption pattern and plasma concentration profiles obtained after subcutaneous administration of the classic pioneer IVM formulation (1%) and two different commercially available IVM-LA preparations (3.15%) to cattle. Twenty-eight Holstein heifers were divided in four experimental groups (n=7) and treated subcutaneously as follows--Group A: IVM 1% given at 200 microg/kg, Group B: IVM 1% administered at 630 microg/kg, Group C: IVM-LA (A) injected at 630 microg/kg and Group D: IVM-LA (B) given at 630 microg/kg. Blood samples were taken between 0.5 and 90 days post-treatment and IVM plasma concentrations were determined by HPLC with fluorescence detection. There were no differences in the persistence of IVM plasma concentrations after the administration of IVM 1% formulation at the two used dose levels (200 and 630 microg/kg). Higher peak plasma concentration (C(max)) and shorter mean residence time (MRT) were obtained for IVM 1% given at 630 microg/kg (Group B) compared to the treatments with both IVM-LA preparations. The IVM-LA (A) formulation showed a more extended absorption process than IVM-LA (B) preparation, which accounted for a longer persistence of detectable IVM plasma concentrations. The parasitological implications of the observed differences in peak plasma concentrations (C(max) values) and in the IVM concentration levels measured from day 20, and afterwards until day 90 post-treatment, between the different preparations assayed need to be elucidated. The characterization of the absorption patterns and kinetic behaviour obtained after injection of these novel long-acting formulations used at three times the therapeutic dose recommended for the classic IVM preparation in cattle is a further contribution to the field.     

Blood and tissue concentrations of trimethoprim following its administration alone and in combination with josamycin.

Following a single oral dose of trimethoprim (10 mg/kg b. wt.) in normal fowls, the highest serum concentration achieved 4 hours post-administration with value of 0.64 microgram/ml. The absorption half-life time was 0.64 hours. The elimination half life was 4.73 hours. During repeated oral administration of 10 mg/kg b. wt., once daily for five consecutive days, trimethoprim peaked in serum, 4 h after each dose. Trimethoprim persisted in all fowl's tissues for 96 hours after stopping of drug administration. After oral administration of josamycin (18 mg/kg b. wt.) and trimethoprim (10 mg/kg b. wt.) in normal fowls, a maximum serum concentration of trimethoprim was recorded at 2 hours with half-life of absorption (t0.5(ab)) valued 0.74 hour. The elimination half-life (t0.5 beta) was 4.37 hours. During repeated oral administration of josamycin (18 mg/kg b. wt.) and trimethoprim (10 mg/kg b. wt.) once daily for five consecutive days in normal fowls, the highest plasma concentrations of trimethoprim occurred 2 hours post each dose. The daily maximum plasma concentrations during the repeated oral administration of both tested drugs were nearly constant.