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.     

Enhancement of moxidectin bioavailability in lamb by a natural flavonoid: quercetin

Moxidectin is an antiparasitic drug widely used in cattle, sheep and companion animals. Due to the involvement of P-glycoprotein (P-gp) and cytochrome P450 3A in the metabolism of moxidectin, we studied the influence of various P-gp interfering agents (ivermectin, quercetin and ketoconazole) on the metabolism of 14C moxidectin in cultured rat hepatocytes over 72 h. This in vitro study allowed selection of compounds which are able to increase the moxidectin bioavailability in lambs. From this, the modulation of moxidectin pharmacokinetics in plasma of lambs was studied after co-administration of 0.2 mg kg(-1) moxidectin (subcutaneously (SC)) and 0.2 mg kg(-1) ivermectin (SC), or 10 mg kg(-1) quercetin (SC), or 10 mg kg(-1) ketoconazole (orally). Ivermectin and quercetin increased significantly the quantity of 14C moxidectin in the rat hepatocytes. Ketoconazole co-administration led to a higher concentration of moxidectin in the rat hepatocytes. In vivo, only quercetin was able to modify the pharmacokinetics of moxidectin in plasma of lambs by increasing significantly the area under the plasma concentration-time curve. This study allowed the use of a natural agent, quercetin, to improve the bioavailability of moxidectin.     

Cetirizine in horses: pharmacokinetics and effect of ivermectin pretreatment

The pharmacokinetics of the histamine H(1)-antagonist cetirizine and the effects of pretreatment with the antiparasitic macrocyclic lactone ivermectin on the pharmacokinetics of cetirizine were studied in horses. After oral administration of cetirizine at 0.2 mg/kg bw, the mean terminal half-life was 3.4 h (range 2.9-3.7 h) and the maximal plasma concentration 132 ng/mL (101-196 ng/mL). The time to reach maximal plasma concentration was 0.7 h (0.5-0.8 h). Ivermectin (0.2 mg/kg bw) given orally 1.5 h before cetirizine did not affect its pharmacokinetics. However, ivermectin pretreatment 12 h before cetirizine increased the area under the plasma concentration-time curve by 60%. The maximal plasma concentration, terminal half-life and mean residence time also increased significantly following the 12 h pretreatment. Ivermectin is an inhibitor of P-glycoprotein, which is a major drug efflux transporter in cellular membranes at various sites. The elevated plasma levels of cetirizine following the pretreatment with ivermectin may mainly be due to decreased renal secretion, related to inhibition of the P-glycoprotein in the proximal tubular cells of the kidney. The pharmacokinetic properties of cetirizine have characteristics which are suitable for an antihistamine, and this substance may be a useful drug in horses.     

The difference in efficacy of ivermectin oral, moxidectin oral and moxidectin injectable formulations against an ivermectin-resistant strain of Trichostrongylus colubriformis in sheep

AIM: To evaluate the efficacy of ivermectin oral, moxidectin oral and moxidectin injectable formulations against an ivermectin-resistant strain of Trichostrongylus colubriformis in sheep. METHODS: Twenty-four mixed breed lambs were infected with 15,000 infective third-stage larvae of an ivermectin-resistant strain of T. colubriformis which had originally been isolated from a goat farm in Northland in 1997. Twenty-six days post infection, the lambs were divided into 3 treatment groups and a control group (n=6 lambs/group). Treatment consisted of either ivermectin oral formulation (0.2 mg/kg), moxidectin oral formulation (0.2 mg/kg), or moxidectin injectable formulation (0.2 mg/kg). Faecal egg counts (FECs) were determined at 0, 3, 5, 7 and 10 days after treatment. All animals were necropsied 12 days after treatment and worm counts were performed. Larval development assays were conducted 24 days post infection. A further 3 lambs were infected with 15,000 infective third-stage larvae of a fully susceptible strain of T. colubriformis for comparative purposes in the larval development assay. The efficacy of the moxidectin injectable formulation was also confirmed in these 3 lambs. RESULTS: The FEC reduction test at day 10 after treatment revealed 62%, 100% and 0% reductions in arithmetic-mean FECs for ivermectin oral, moxidectin oral and moxidectin injectable groups, respectively. The ivermectin oral, moxidectin oral and moxidectin injectable formulations achieved 62%, 98% and 4% reductions in arithmetic-mean worm burdens, respectively. Larval development assays showed resistance ratios for ivermectin of 4:1, avermectin B2 of 2.7:1, ivermectin aglycone of 37:1, moxidectin of 1.4:1, thiabendazole of 14.6:1 and levamisole of 1.8:1. CONCLUSIONS: The moxidectin oral formulation provided a high degree of control against ivermectin-resistant T. colubriformis whereas the moxidectin injectable formulation had very low efficacy. Ivermectin aglycone was the analogue of choice for diagnosis of ivermectin resistance in T. colubriformis in the larval development assay.     

Pharmacokinetics, tolerance and serum thromboxane inhibition of carprofen in the dog

The non-steroidal anti-inflammatory drug (NSAID) carprofen was administered to dogs as a mixed-micelle solution at a dose rate of 0–7 mg/kg intravenously, as a palatable paste at a dose rate of 0–7 mg/kg orally, and as an oral tablet formulation at a dose rate of 0–7 mg/kg and 4-0 mg/kg orally for pharmacokinetic studies. It was also administered as an oral tablet formulation at a dose rate of 9-0 mg/kg orally daily for 14 days in a tolerance study. The pharmacokinetics following intravenous administration at a dose rate of 0–7 mg/kg indicate that carprofen has a small volume of distribution (Vd area = 0–09-0-25 litres), a slow systemic clearance (Cls = 1–34-5-57 ml/min) and an elimination half-life of 3–20-11-77 hours. Both oral paste and tablet preparations were highly bioavailable and absorption was proportional to dose rate at 0–7 mg/kg and 4-0 mg/kg bodyweight. Given once daily at dose rates likely to be used clinically it is unlikely to accumulate in the plasma. Carprofen administered as a palatable paste at a dose rate of 0–7 mg/kg did not inhibit serum thromboxane generation and this drug may therefore have a mode of action different from most NSAIDs. Carprofen was well tolerated when administered as an oral tablet formulation at a dose rate of 9.0 mg/kg daily for 14 days in healthy beagle dogs.     

The pharmacokinetics of ketoconazole and its effects on the pharmacokinetics of midazolam and fentanyl in dogs

KuKanich, B., Hubin, M. The pharmacokinetics of ketoconazole and its effects on the pharmacokinetics of midazolam and fentanyl in dogs. J. vet. Pharmacol. Therap . 33 , 42–49.
Ketoconazole inhibits the Cytochrome P450 3A12 (CYP3A12) metabolizing enzyme as well as the p-glycoprotein efflux pump. The extent and clinical consequence of these effects are poorly understood in dogs. The objective was to assess the pharmacokinetics of ketoconazole after single and multiple doses and the effect of multiple doses of ketoconazole on midazolam (a known CYP3A12 substrate) and the opioid fentanyl. Six greyhound dogs were studied. The study consisted of three phases. Phase 1 consisted of i.v. midazolam (0.23 mg/kg base) and fentanyl (15.71 μg/kg base). Phase 2 consisted of a single oral dose of ketoconazole (mean dose 12.34 mg/kg). Phase 3 consisted of i.v. midazolam (0.23 mg/kg) and fentanyl (10 μg/kg) after 5 days of oral ketoconazole (12.25 mg/kg/day). Ketoconazole significantly inhibited its own elimination with the mean residence time ( MRT ) increasing from 6.24 h in Phase 1 to 12.54 h in Phase 3. Ketoconazole significantly decreased the elimination of midazolam, as expected, with the MRT increasing from 0.81 to 1.49 h. The elimination of fentanyl was not significantly altered by co-administration of ketoconazole with the MRT being 3.90 and 6.35 h. The MRT was the most robust estimate of decreased drug elimination.     

Effect of Ketoconazole on Cyclosporine Dose in Healthy Dogs

Objective—To determine the degree to which the dose of oral cyclosporine (CyA), in healthy dogs, can be decreased by concurrent oral administration of ketoconazole. Dogs in this study were observed for physical or biochemical side effects that might have been caused by the administration of CyA and ketoconazole. Study Design—Prospective research study. Sample Population—Five healthy, intact female Beagle dogs. Methods—CyA was administered orally twice daily to achieve stable whole blood trough levels of 400 to 600 ng/mL. Ketoconazole was added at a low therapeutic dose (average dose: 13.6 mg/kg/d) then at a subtherapeutic dose (average dose: 4.7 mg/kg/d). CyA whole blood trough levels were monitored every 3 to 4 days and maintained at 400 to 600 ng/mL by adjusting CyA doses accordingly. Physical examination, CBC, biochemical profile, and urinalysis were performed at 2-week intervals throughout the study period. Results—The initial mean dose of CyA required to achieve target blood levels was 14.5 mg/ kg/d. With concurrent ketoconazole (low therapeutic dose, average dose: 13.6 mg/kg/d) and CyA administration, the CyA dose declined to 3.4 mg/kg/day (range: 1.2 to 5.2 mg/kg/d), representing a 75% reduction in CyA dose and monetary savings of 57.8%. At a subtherapeutic dose of ketoconazole (average dose: 4.7 mg/kg/d), combination therapy resulted in a CyA dose of 10.1 mg/kg/day (4.9 to 10.6 mg/kg/d), representing a 38% reduction in CyA dose and monetary savings of 23.8%. Weight loss and transient hypoalbuminemia of unknown clinical significance were observed. Other physical and biochemical evaluations were unremarkable over the 12-week study period. Conclusions—The oral administration of ketoconazole can be used to reduce substantially the oral CyA dose needed to maintain selected blood levels in healthy dogs. Clinical Relevance—The oral administration of ketoconazole can result in substantial cost savings to owners of dogs receiving CyA after renal allograft transplantation or for the treatment of autoimmune disease.     

Brain penetration of ivermectin and selamectin in mdr1a,b P-glycoprotein- and bcrp- deficient knockout mice

P-glycoprotein, which is encoded by the multi-drug resistance gene (MDR1), highly restricts the entry of ivermectin into the brain by an ATP-driven efflux mechanism at the blood–brain barrier. In dogs with a homozygous MDR1 mutation though, ivermectin accumulates in the brain and provokes severe signs of neurotoxicosis and even death. In contrast to ivermectin, selamectin is safer in the treatment of MDR1 mutant dogs, suggesting that selamectin is transported differently by P-glycoprotein across the blood–brain barrier. To test this, we applied selamectin to mdr1-deficient mdr1a,b ^−/− knockout mice and wild-type mice. Brain penetration, organ distribution, and plasma kinetics were analyzed after intravenous, oral, and dermal spot-on application in comparison with ivermectin. We found that in vivo both macrocyclic lactone compounds are substrates of P-glycoprotein and that these strongly accumulate in the brain of mdr1a,b ^−/− knockout mice compared with wild-type mice at therapeutic doses of 12 mg/kg selamectin and 0.2 mg/kg ivermectin. However, selamectin accumulates to a much lesser degree (5–10 times) than ivermectin (36–60 times) in the absence of P-glycoprotein. This could explain the broader margin of safety of selamectin in MDR1 mutant dogs. In liver, kidney, and testes, ivermectin and selamectin accumulated less than four times as much in mdr1a,b mutant mice as in wild-type mice. Breast cancer resistance protein (Bcrp)-deficient bcrp ^−/− knockout mice were also included in the application studies, but showed no differences in brain concentrations or organ distribution of either ivermectin or selamectin compared with wild-type mice. This indicates that Bcrp is not a relevant efflux carrier for these macrocyclic lactone compounds in vivo at the blood–brain barrier.     

Neurotoxic effects of ivermectin administration in genetically engineered mice with targeted insertion of the mutated canine ABCB1 gene

Objective-To develop in genetically engineered mice an alternative screening method for evaluation of P-glycoprotein substrate toxicosis in ivermectin-sensitive Collies. Animals-14 wild-type C57BL/6J mice (controls) and 21 genetically engineered mice in which the abcb1a and abcb1b genes were disrupted and the mutated canine ABCB1 gene was inserted. Procedures-Mice were allocated to receive 10 mg of ivermectin/kg via SC injection (n = 30) or a vehicle-only formulation of propylene glycol and glycerol formal (5). Each was observed for clinical signs of toxic effects from 0 to 7 hours following drug administration. Results-After ivermectin administration, considerable differences were observed in drug sensitivity between the 2 types of mice. The genetically engineered mice with the mutated canine ABCB1 gene had signs of severe sensitivity to ivermectin, characterized by progressive lethargy, ataxia, and tremors, whereas the wild-type control mice developed no remarkable effects related to the ivermectin. Conclusions and Clinical Relevance-The ivermectin sensitivity modeled in the transgenic mice closely resembled the lethargy, stupor, disorientation, and loss of coordination observed in ivermectin-sensitive Collies with the ABCB1-1Δ mutation. As such, the model has the potential to facilitate toxicity assessments of certain drugs for dogs that are P-glycoprotein substrates, and it may serve to reduce the use of dogs in avermectin derivative safety studies that are part of the new animal drug approval process.     

A pilot study of the efficacy of topical ivermectin against lungworm in young red deer (Cervus elaphus)

Three groups of ten 4-month-old red deer (Cervus elaphus) calves naturally infected with lungworm (Dictyocaulus viviparus) were treated with either oral ivermectin (200 microg/kg), topical (pour-on) ivermectin (500 microg/kg) or oral oxfendazole (5 mg/kg). Faecal larval counts for lungworm were undetectable or very low for 14 days after treatment with oxfendazole, 28 days after treatment with oral ivermectin and for 49 days after treatment with topical ivermectin. This pilot study suggests that the topical formulation of ivermectin was very effective against lungworm and had a more persistent action than the oral ivermectin formulation in young red deer.     

Pharmacokinetics of pentoxifylline in dogs after oral and intravenous administration

OBJECTIVE: To evaluate the pharmacokinetics of pentoxifylline (PTX) and its 5-hydroxyhexyl-metabolite, metabolite 1 (M1), in dogs after IV administration of a single dose and oral administration of multiple doses. ANIMALS: 7 sexually intact, female, mixed-breed dogs. PROCEDURE: A crossover study design was used so that each of the dogs received all treatments in random order. A drug-free period of 5 days was allowed between treatments. Treatments included IV administration of a single dose of PTX (15 mg/kg of body weight), oral administration of PTX with food at a dosage of 15 mg/kg (q 8 h) for 5 days, and oral administration of PTX without food at a dosage of 15 mg/kg (q 8 h) for 5 days. Blood samples were taken at 0.25, 0.5, 1, 1.5, 2, 2.5, and 3 hours after the first and last dose of PTX was administered PO, and at 5, 10, 20, 40, 80, and 160 minutes after PTX was administered IV. RESULTS: PTX was rapidly absorbed and eliminated after oral administration. Mean bioavailability after oral administration ranged from 15 to 32% among treatment groups and was not affected by the presence of food. Higher plasma PTX concentrations and apparent bioavailability were observed after oral administration of the first dose, compared with the last dose during the 5-day treatment regimens. CONCLUSIONS AND CLINICAL RELEVANCE: In dogs, oral administration of 15 mg of PTX/kg results in plasma concentrations similar to those produced by therapeutic doses in humans, and a three-times-a-day dosing regimen is the most appropriate.     

Influence of the route of administration on efficacy and tissue distribution of ivermectin in goat

The tissue concentration and efficacy of ivermectin after per os and subcutaneous administration were compared in goats experimentally infected with Trichostrongylus colubriformis (ivermectin-susceptible strain, INRA). Infected goats (n = 24) were treated per os (n = 9) or subcutaneously (n = 9) with ivermectin, 0.2 mg/kg, or kept as not treated controls. The faecal egg counts and small intestine worm counts were determined. Ivermectin concentration was measured in the plasma, gastrointestinal tract, lung, skin or hair, liver and adipose tissues at 0, 2, 7 and 17 days post-treatment. The efficacy of ivermectin against T. colubriformis infection in goat was 98.7 and 99.9% for subcutaneous and oral administration, respectively. Ivermectin concentration declined with time and only residual concentration was measured at 17 days post-treatment in plasma and gastrointestinal tract. Ivermectin concentration was higher after subcutaneous compared to per os injection in most of the tissue examined. In skin, hair and subcutaneous adipose tissue ivermectin persisted at significant concentrations 17 days post-treatment for both routes of administration. In our experimental conditions, ivermectin provides similar efficacy against T. colubriformis after subcutaneous or per os administration in goat. However, the lower ivermectin levels in tissues after per os administration suggest that the lasting of efficacy may be shortened after per os compared to subcutaneous administration especially in animals with poor body condition in pasture where re-infection occurs quickly after anthelmintic treatment.     

Failure of ivermectin and eprinomectin to control Amblyomma parvum in goats: characterization of acaricidal activity and drug pharmacokinetic disposition

The therapeutic efficacies of ivermectin (subcutaneous injection) and eprinomectin (topical treatment) given at two different dosage levels to goats naturally infested with Amblyomma parvum were assessed. Treatments included subcutaneous injection of ivermectin at 0.2 and 0.4mg/kg and extra-label pour-on administration of eprinomectin at 0.5 and 1mg/kgb.w. Ivermectin and eprinomectin failed to control Amblyomma parvum on goats. Treatment with ivermectin resulted in a low number of engorged female ticks in relation to untreated control goats and, at the highest dose rate (0.4mg/kg), the female engorgement weights were significantly lower and the pre-oviposition period significantly longer than those observed in ticks recovered from untreated control goats. The tick efficacy assessment was complemented in a separate group of tick-free goats with a pharmacokinetic characterization of eprinomectin (topically administered at 0.5, 1.0 and 1.5mg/kg) and ivermectin (subcutaneous treatment given at (0.2 and 0.4mg/kg) in goats. Heparinized blood samples were taken between 0 and 21 days post-treatment. Higher and more persistent drug plasma concentrations were recovered after the subcutaneous treatment with ivermectin compared to those obtained for eprinomectin topically administered. The understanding of the relationship among the pattern of drug absorption, the kinetic disposition and the resultant clinical efficacy is relevant to improve the poor performance observed for ivermectin and eprinomectin against A. parvum on goats.     

Evaluation of the dosage of ivermectin in falcons

Twelve groups of falcons, each containing three female gyrfalcon-peregrine falcon hybrids (Falco rusticolus x Falco peregrinus) were injected intramuscularly with a single dose of ivermectin ranging from 0.2 mg/kg to 11 mg/kg bodyweight, and a control group was injected with water. Doses of ivermectin between 0.2 and 5 mg/kg failed to produce clinical signs of illness in the birds. Four birds which received either 6, 7 or 8 mg/kg showed slight clinical signs, and all the birds receiving 9 to 11 mg/kg showed more or less severe clinical signs of anorexia, apathy and sedation. Slight changes in the mean plasma activities of aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase (AP) were detected in the group dosed with 5 mg/kg, and higher dosages caused marked changes in these enzymes as well as in the mean plasma activity of lactate dehydrogenase. The mean activity of AP decreased, and the activities of the other enzymes increased. A dosage of 2 to 3 mg/kg ivermectin is recommended as a safe and effective antiparasitic drug for falcons and it has been used successfully to treat infestations of Serratospiculum species.     

Effect of subacute oral doses of nivalenol on immune and metabolic defence systems in mice

Nivalenol (NIV) is a toxic Fusarium secondary trichothecene metabolite occurring naturally in cereal grains. In order to evaluate the no observed adverse effect level (NOAEL), we tested the effects of a large array of oral doses of this toxin for responses on plasma biochemistry, the immune system and hepatic drug metabolism in mice. C57Bl6 mice received oral doses of toxin (0.014, 0.071, 0.355, 1.774 or 8.87 mg/kg bw) 3 days a week for 4 weeks. Only the highest dose of NIV induced an increase in plasma phosphate, decreases in plasma urea and immunoglobulin M and additional changes like increases in plasma alkaline phosphatase and immunoglobulin G. Interleukin 4 production was increased in cultured murine splenocytes. Regarding liver drug metabolising enzymes, the only glutathione transferase activity accepting 1-chloro-2,4-dinitro-benzene as substrate was transiently increased in mice receiving low doses (0.071 and 0.355 mg/kg bw) of NIV. Regarding the cytochrome P450 monooxygenases, no significant change was observed in ethoxyresorufin O-deethylase activity whereas both methoxyresorufin and pentoxyresorufin O-dealkylase activities were decreased by 38-45% for the highest dose (8.87 mg/kg bw) of NIV. However, when analysed by Western blot analysis, the protein expression of mouse P450 1a, 2b, 2c, 3a and 4a subfamilies was unchanged in animals receiving NIV. In conclusion, the NOAEL of this toxin in our study was 1.774 mg/kg bw, corresponding to an exposure to 5 ppm contaminated food. Indeed hepatotoxicity appears in the only mice treated with a five fold higher oral dose of 8.87 mg/kg bw of NIV. Such exposure levels appear to be by far higher than the maximal natural occurrence measured in European cereals, known to range from 0.34 to 1.86 ppm.     

Comparison of the pharmacokinetics of moxidectin (Equest®) and ivermectin (Eqvalan®) in horses

A study was undertaken in order to evaluate and compare plasma disposition kinetic parameters of moxidectin and ivermectin after oral administration of their commercially available preparations in horses. Ten clinically healthy adult horses, weighing 390-446 kg body weight (b.w.), were allocated to two experimental groups of five horses. Group I was treated with an oral gel formulation of moxidectin (MXD) at the manufacturers recommended therapeutic dose of 0.4 mg/kg bw. Group II was treated with an oral paste formulation of ivermectin (IVM) at the manufacturers recommended dose of 0.2 mg/kg b.w. 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 HPLC with fluorescence detection. Computerized kinetic analysis was carried out. The parent molecules were detected in plasma between 30 min and either 30 (IVM) or 75 (MXD) days post-treatment. Both drugs showed similar patterns of absorption and no significant difference was found for the time corresponding to peak plasma concentrations or for absorption half-life. Peak plasma concentrations (Cmax) of 70.3+/-10.7 ng/mL (mean +/- SD) were obtained for MXD and 44.0+/-23.1 ng/mL for IVM. Moreover, the values for area under concentration-time curve (AUC) were 363.6+/-66.0 ng x d/mL for the MXD treated group, and 132.7+/-47.3 ng x d/mL for the IVM treated group. The mean plasma residence times (MRT) were 18.4+/-4.4 and 4.8+/-0.6 days for MXD and IVM treated groups, respectively. The results showed a more prolonged residence of MXD in horses as demonstrated by a four-fold longer MRT than for IVM. The longer residence and the higher concentrations found for MXD in comparison to IVM could possibly explain a more prolonged anthelmintic effect. It is concluded that in horses the commercial preparation of MXD presents a pharmacokinetic profile which differs significantly from that found for a commercial preparation of IVM. To some extent these results likely reflect differences in formulation and doses.     

Pharmacokinetics of fenbendazole in dogs

Fenbendazole was administered to dogs at a dose rate of 20 mg/kg body weight on a single occasion in gelatin capsules, on 5 consecutive days in feed, and on a single occasion as an alginate suspension. It was also administered at a dose rate of 100 mg/kg body weight on a single occasion in feed. Following single administration of 20 mg/kg fenbendazole mean maximum concentrations (Cmax) of the parent drug and its known active sulphoxide metabolite were 0.42 +/- 0.05 and 0.31 +/- 0.05 microgram/ml, respectively. Mean times until maximum concentrations were achieved (tmax) were 12.67 +/- 4.18 and 15.33 +/- 2.81 h, respectively, and areas under the plasma concentration-time curves (AUC) were 5.83 +/- 0.65 and 4.60 +/- 0.57 microgram.h/ml, respectively. Administration in feed increased the apparent bioavailability and administration for 5 consecutive days provided sustained plasma concentrations, generally greater than 0.2 microgram/ml. Administration as an alginate did not increase bioavailability or extend the persistence in plasma. It did increase the tmax to 16.80 +/- 2.93 and 20.00 +/- 2.53 h for fenbendazole and its sulphoxide metabolite, respectively. Increasing the dose from 20 mg/kg to 100 mg/kg did not substantially increase the Cmax or AUC.     

Intramuscular and oral disposition of enrofloxacin in African grey parrots following single and multiple doses

The intramuscular (IM) and oral (PO) disposition of enrofloxacin, a new fluoroquinolone antimicrobial drug, were evaluated in African grey parrots. Peak enrofloxacin concentration, mean (+/- SEM), at 1 h following a 15-mg/kg IM dose was 3.87 (+/- 0.27) micrograms/ml and declined with a mean residence time of 3.05 h. Peak enrofloxacin plasma concentrations at 2 to 4 h following oral doses of 3, 15, and 30 mg/kg were 0.31 (+/- 0.11), 1.12 (+/- 0.11), and 1.69 (+/- 0.23) micrograms/ml, respectively, and declined with a mean residence time of 3.44-5.28 h. The relative bioavailability of the 15-mg/kg oral dose was 48%. An equipotent metabolite, ciprofloxacin, was detected in plasma at concentrations ranging from 3 to 78% of those of enrofloxacin. Enrofloxacin concentrations and area under the curve were significantly lower, the mean residence time significantly shorter and the ciprofloxacin/enrofloxacin ratios higher, following 10 days of oral treatment at 30 mg/kg every 12 h. Following 10 days of treatment, no significant biochemical changes were noted; however, polydipsia and polyuria occurred in treated birds, but resolved quickly upon discontinuation of enrofloxacin administration. These studies indicate that a rational starting dose for enrofloxacin in psittacines (7.5-30 mg/kg BID) should be higher than those in other domestic animals.     

Plasma and interstitial fluid pharmacokinetics of enrofloxacin, its metabolite ciprofloxacin, and marbofloxacin after oral administration and a constant rate intravenous infusion in dogs

Enrofloxacin and marbofloxacin were administered to six healthy dogs in separate crossover experiments as a single oral dose (5 mg/kg) and as a constant rate IV infusion (1.24 and 0.12 mg/h.kg, respectively) following a loading dose (4.47 and 2 mg/kg, respectively) to achieve a steady-state concentration of approximately 1 microg/mL for 8 h. Interstitial fluid (ISF) was collected with an in vivo ultrafiltration device at the same time period as plasma to measure protein unbound drug concentrations at the tissue site and assess the dynamics of drug distribution. Plasma and ISF were analyzed for enrofloxacin, its active metabolite ciprofloxacin, and for marbofloxacin by high performance liquid chromatography (HPLC). Lipophilicity and protein binding of enrofloxacin were higher than for marbofloxacin and ciprofloxacin. Compared to enrofloxacin, marbofloxacin had a longer half-life, higher Cmax, and larger AUC(0-infinity) in plasma and ISF after oral administration. Establishing steady state allowed an assessment of the dynamics of drug concentrations between plasma and ISF. The ISF and plasma-unbound concentrations were similar during the steady-state period despite differences in lipophilicity and pharmacokinetic parameters of the drugs.     

Pharmacokinetics of ivermectin in pregnant and nonpregnant sheep

The plasma kinetic profile of ivermectin during the last trimester of pregnancy was studied in ewes after a single subcutaneous administration of 0.2 mg/kg body weight (BW). Sheep were randomly distributed into two groups. Ewes in group 1 (control, n=6) were left unmated, whereas in group 2 (pregnant, n=6) ewes were estrus-synchronized and mated with rams. Both groups were housed under similar conditions of management and feeding. At 120 days of pregnancy, both groups were given a subcutaneous injection of 0.2 mg/kg BW of ivermectin. Blood samples were taken by jugular puncture according to a fixed protocol between 1 h and 40 days post-treatment. After plasma extraction and derivatization, samples were analyzed by high performance liquid chromatography with fluorescence detection. A computerized pharmacokinetic analysis was performed, and the data were compared by means of the Student t-test. The results showed that plasma concentrations of ivermectin remained longer in the pregnant than in the control group. The mean values of pharmacokinetic parameters C(max), t(max), and area under the concentration-time curve (AUC) were similar for both groups of sheep. The mean residence time (MRT) values for the pregnant group (8.8+/-1.4 days) were higher (P<0.05) than those observed in the control group (5.3+/-1.9 days). It can be concluded that pregnancy increases the residence time of ivermectin in the plasma of pregnant sheep when it is administered subcutaneously.