Selection for resistance to macrocyclic lactones by Haemonchus contortus in sheep.

An anthelmintic-sensitive Haemonchus contortus strain was selected for moxidectin and ivermectin resistance concurrently for 22 generations. Treatment with 0.002 mg moxidectin/kg BW or 0.02 mg ivermectin/kg BW produced >99% efficacy against the susceptible parent strain passaged for 22 generations without any anthelmintic exposure. However, to obtain similar efficacy the moxidectin-selected and the ivermectin-selected strains of H. contortus required 0.05 mg moxidectin/kg BW or 0.4 mg ivermectin/kg BW. These results indicate that development of resistance to one macrocyclic lactone, simultaneously results in resistance to another macrocyclic lactone. However, rates of resistance development differ between compounds and occurs more slowly with moxidectin than with ivermectin.     

Efficacy of moxidectin, nemadectin and ivermectin against an ivermectin-resistant strain of Haemonchus contortus in sheep.

The efficacies of ivermectin, nemadectin and moxidectin were evaluated when administered orally to lambs infected with either a susceptible laboratory strain of Haemonchus contortus or a strain reported to be resistant to ivermectin. Groups of 24 Dorset cross Cheviot cross Suffolk lambs were infected with either the susceptible or resistant strain of H contortus and allocated to treatment groups according to their faecal egg counts 27 days after infection. One day later the lambs were dosed orally with one of the three anthelmintics at 0.2 mg/kg bodyweight, and they were killed and surviving worms were recovered 13 or 14 days after treatment. Against the ivermectin resistant strain, ivermectin did not significantly reduce the egg count or the numbers of adult H contortus; however, both nemadectin and moxidectin reduced the nematode egg counts and the numbers of H contortus by 99 and 100 per cent, respectively. Against the susceptible strain, all the anthelmintics reduced the egg counts by 100 per cent as early as four days after treatment and reduced the numbers of susceptible H contortus by 100 per cent. No adverse reactions to any of the drugs were observed.     

Efficacy of moxidectin against an ivermectin-resistant strain of Haemonchus contortus in sheep.

The efficacy of moxidectin was determined against ivermectin-susceptible and resistant strains of Haemonchus contortus. At the onset of the trial, 40 lambs were each infected with 5000 third stage larvae of one of two strains of Haemonchus contortus. The lambs were randomly sorted into eight treatment groups 28 days post-infection and were treated as follows: Group 1, susceptible strain with no treatment; Group 2, resistant strain with no treatment; Group 3, susceptible strain treated with 0.2 mg moxidectin kg-1 body weight; Group 4, resistant strain treated with 0.2 mg moxidectin kg-1; Group 5, resistant strain treated with 0.4 mg moxidectin kg-1; Group 6, susceptible strain treated with 0.2 mg ivermectin kg-1; Group 7, resistant strain treated with 0.4 mg ivermectin kg-1; Group 8, resistant strain treated with 0.8 mg ivermectin kg-1. The lambs were killed 1 week post-treatment. Comparisons were made among groups based on the number of eggs per gram of feces on the day of treatment and the numbers of worms recovered from each lamb. Both moxidectin and ivermectin were effective in removing susceptible Haemonchus with efficacies of 100% and 99.7%, respectively. The efficacy of moxidectin against the resistant strain was 99.9% and 100% at 0.2 mg kg-1 and 0.4 mg kg-1, respectively, whereas there were only 38.8% and 53.1% efficacies in the lambs treated with 0.4 mg ivermectin kg-1 and 0.8 mg kg-1 body weight, respectively.     

Reduced efficacy of ivermectin, abamectin and moxidectin against field isolates of Haemonchus contortus

OBJECTIVES: To investigate the reduced efficacy of ivermectin, abamectin and moxidectin against two field isolates of Haemonchus contortus. These isolates were identified on separate properties in the New England region of New South Wales. PROCEDURE: Reduced efficacy of macrocyclic lactone anthelmintics against two field isolates of H contortus was suspected. These isolates were obtained from sheep on separate farms and pen trials were performed to investigate the efficacy of macrocyclic lactones. The percentage efficacy was calculated for moxidectin, ivermectin and closantel against the isolate from one farm (VHR23) and for moxidectin, ivermectin and abamectin against the isolate from the second (VHR29). The persistent activity of moxidectin against both isolates was investigated. RESULTS: Ivermectin and closantel were found to have efficacies below 80% against established populations of VHR23. Moxidectin was effective against an established population of VHR23 but the persistent activity was reduced to 7 days. Moxidectin was also found to be effective against established populations of VHR29, however, ivermectin and abamectin were found to have efficacies below 80%. There was no evidence of persistent activity of moxidectin against VHR29. CONCLUSION: A reduction in efficacy of abamectin and/or ivermectin against field isolates of H. contortus was identified from two farms in the New England region of New South Wales. The persistent effect of moxidectin was reduced against both isolates.     

Duration of the persistent activity of moxidectin against Haemonchus contortus in sheep

SUMMARY Weaned lambs were infected with Haemonchus contortus 35,28,21,14 and 7 days after treatment with moxidectin at 0.2 mg/kg and 35 and 14 days after treatment with ivermectin at the same dose rate. Worm counts 14 days after infection showed that moxidectin prevented the establishment of over 99% of infective larvae for 28 days and reduced the establishment rate at 35 days by 96%, relative to ivermectin. There was no difference in the protective efficacy of ivermectin at 14 or 35 days. The persistence of moxidectin is likely to provide advantages in nematode control, particularly when used as a strategic early summer treatment or as a pre-lambing treatment to ewes. Implications of the persistent activity of moxidectin for the development of resistance during the decay phase are discussed.     

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.     

The effects of ivermectin and moxidectin on egg viability and larval development of ivermectin-resistant Haemonchus contortus

The in vivo effects of ivermectin and moxidectin on egg viability and larval development of ivermectin-resistant Haemonchus contortus were examined over time after anthelmintic treatment of sheep. Twenty merino sheep, (12 months old) were allocated to five treatment groups and infected with ivermectin-resistant H. contortus. Thirty one days later, the sheep were treated with intraruminal ivermectin capsules, oral ivermectin, oral moxidectin or injectable moxidectin at the manufacturer's recommended dosages, or left untreated. At various times up to 112 days after treatment, faecal egg counts (FEC) were determined and development rates of infective larvae (L3) cultured in faeces or on agar were measured. Eggs in faecal cultures from ivermectin capsule treated sheep showed reduced L3 development percentages in comparison to faecal cultures from untreated sheep. Eggs from ivermectin capsule treated sheep, isolated from faeces, and cultured on agar showed similar L3 development to eggs from control sheep. These results demonstrate an inhibitory effect of excreted ivermectin in faeces on larval development of ivermectin-resistant H. contortus. L3 development in faecal culture from animals receiving oral ivermectin were reduced for only 3 days after treatment. Faecal egg counts and development of L3 larvae in both culture systems from moxidectin treated sheep were low, due to the high efficacy of the drug. Egg counts in moxidectin treated sheep were reduced by approximately 90% 24h after treatment, before decreasing to almost 100% at 48h, suggesting that the current quarantine recommendation of holding sheep off pasture for 24h after treatment may still lead to some subsequent pasture contamination with worm eggs.     

Efficacy of albendazole and moxidectin and resistance to ivermectin against Libyostrongylus douglassii and Libyostrongylus dentatus in ostriches

Anthelmintic resistance has emerged globally as a problem amongst nematode of livestock and has been particularly well documented in equine and small ruminants. There are no studies regarding the efficacy of anthelmintics against the hematophagous nematodes in ostriches, Libyostrongylus dentatus; and just a few on L. douglassii. Here the efficacy of albendazole, ivermectin and moxidectin were evaluated against these two species in an ostrich farm in Minas Gerais state, Brazil. The feces were collected on the day of treatment and after 13days of an oral dose of albendazole (6mg/kg), or an injected dose (0.2mg/kg) of ivermectin or moxidectin. The fecal egg count reduction test and coprocultures were performed to determine possible resistance against the drugs used. An efficacy of 60% was found for ivermectin, while albendazole and moxidectin were 100% effective. Both worm species appeared to have reduced sensitivity to ivermectin.     

Characterization of moxidectin resistant Trichostrongylus colubriformis and Haemonchus contortus

The development of moxidectin resistance (MOX-R) in sheep parasitic gastrointestinal nematodes already carrying multiple resistances to other anthelmintic groups has made control of these strains very difficult. The anthelmintic resistance patterns of MOX-R strains of Trichostrongylus colubriformis and Haemonchus contortus were characterized to provide an insight into the remaining role of anthelmintics in the control of such strains. Homozygous MOX-R individuals of both genera were unaffected by moxidectin. For MOX-R heterozygotes a dose rate of 200 microg/kg abamectin (ABA) given orally removed 25% of H. contortus while 200 microg/kg MOX given orally achieved a 72% reduction. Doubling the dose rate of ABA improved the mean efficacy to 37%. Consequently, in H. contortus, the degree of dominance differs markedly between the two anthelmintics. A dose rate of 8 mg/kg levamisole and 185 mg/kg napthalophos achieved >95% reduction in worm count of the MOX-R homozygous H. contortus but only 85 and 7%, respectively against the MOX-R homozygous T. colubriformis.     

Efficacy of moxidectin and other anthelmintics against small strongyles in horses

Objective To compare the efficacy of moxidectin to ivermectin, oxibendazole and morantel against some gastrointestinal nematodes in horses.
Design Faecal egg count reduction after treatment.
Procedure A farm was selected where the population of small strongyles in horses was known to be resistant to oxibendazole. Horses were allocated to treatment groups based on faecal egg counts. After treatment, faecal samples were taken up to 109 days after treatment and faecal egg counts estimated. Faecal cultures were used to estimate the contribution of small and large strongyles to the faecal egg counts at each sampling.
Results Moxidectin (0.4 mg/kg) suppressed faecal egg counts for 109 days after treatment in most horses compared to 40 days with ivermectin (0.2 mg/kg), 13 days with morantel (9.4 mg/kg) and less than 13 days with oxibendazole (10 mg/kg). Most of the faecal egg count was attributable to small strongyles based on faecal culture, although Strongylus vulgaris was present in some samples in low numbers. Oxibendazole resistance in small strongyles was confirmed and a less than expected efficacy of morantel was also seen.
Conclusion Moxidectin was highly effective in reducing faecal egg counts after treatment for at least 12 weeks and up to 16 weeks in most horses. These horses were infected with a population of small strongyles known to be resistant to oxibendazole and possibly morantel. The duration of the reduction in faecal egg counts after treatment with moxidectin (0.4 mg/kg) was at least twice that of ivermectin (0.2 mg/kg) and greater than four times that for morantel and oxibendazole.     

A review of the use of moxidectin in horses

Moxidectin has broad‐spectrum anti‐nematodal and anti‐arthropodal activities in the horse but is not effective against tapeworms or flukes. Moxidectin and ivermectin have the same efficacy against internal, adult parasites of horses. Moxidectin, however, is highly effective in eliminating encysted and hypobiotic larval stages of cyathostomins, whereas ivermectin is not. Treatment of horses with moxidectin results in an egg‐reappearance period (ERP) of 15–24 weeks. Because of its long ERP, moxidectin is labelled to be used at 12 week intervals. Moxidectin may provide protection against infection by ingested cyathostomin larvae for 2–3 weeks after it is administered. The larvicidal activity of moxidectin has often been compared to that of fenbendazole administered at either 7.5 or 10 mg/kg bwt for 5 consecutive days. The efficacy of fenbendazole, when administered daily for 5 consecutive days at 7.5 or 10 mg/kg bwt, against all stages of cyathostomins is often less than that of moxidectin because resistance of cyathostomins to benzimidazoles is prevalent worldwide, and the 5 day course of fenbendazole does not overcome this resistance. There are now reports of resistance of ascarids to moxidectin. Overt resistance of cyathostomins and a shortened egg re‐emergence period after treatment with moxidectin have been reported. Rapid removal of manure by natural fauna can significantly reduce larval nematode concentrations and thereby reduce intervals of anthelmintic treatment. Of the macrocyclic lactones, moxidectin has the least deleterious effect on faecal fauna.     

Efficacy of ivermectin and moxidectin against Otostrongylus circumlitus and Parafilaroides gymnurus in harbour seals (Phoca vitulina)

Verminous bronchopneumonia caused by infection with Otostrongylus circumlitus and Parafilaroides gymnurus is an important cause of death during the rehabilitation of harbour seals (Phoca vitulina). During the winter of 2000/01, 35 juvenile harbour seals with severe clinical signs of verminous bronchopneumonia were treated with either 0.2 mg/kg ivermectin orally or 0.2 mg/kg moxidectin subcutaneously, and monitored for 30 days. The efficacy of the anthelmintics was determined by the pattern of larval excretion (Baermannisation) and the progress of the clinical signs. Both anthelmintics had reduced larval excretion by at least 99 per cent after 10 days, but the seals' rapid breathing rate and and dyspnoea returned to normal more quickly in the animals treated with moxidectin. The pharmacokinetics of the anthelmintics were determined by solid-phase extraction, and high-performance liquid chromatography with fluorescence detection. Moxidectin had a mean (sd) residence time of 9.04 (2.12) days compared with 4.83 (1.14) days for ivermectin.     

Safety of moxidectin in avermectin-sensitive collies

OBJECTIVE: To evaluate the safety of moxidectin administration at doses of 30, 60, and 90 microg/kg of body weight (10, 20, and 30 times the manufacturer's recommended dose) in avermectin-sensitive Collies. ANIMALS: 24 Collies. PROCEDURE: Collies with mild to severe reactions to ivermectin challenge (120 mg/kg; 20 times the recommended dose for heartworm prevention) were used. Six replicates of 4 dogs each were formed on the basis of body weight and severity of reaction to ivermectin test dose. Within replicates, each dog was randomly allocated to treatment with oral administration of 30, 60, or 90 microg of moxidectin/kg or was given a comparable volume of placebo tablet formulation. Dogs were observed hourly for the first 8 hours and twice daily thereafter for 1 month for signs of toxicosis. RESULTS: Signs of toxicosis were not observed in any control group dog throughout the treatment observation period. Likewise, signs of toxicosis were not observed in any dog receiving moxidectin at 30, 60, or 90 microg/kg. CONCLUSIONS AND CLINICAL RELEVANCE: The moxidectin formulation used in the study reported here appears to have a wider margin of safety than ivermectin or milbemycin in avermectin-sensitive Collies.     

Resistance to macrocyclic lactone anthelmintics by Haemonchus contortus and Ostertagia circumcincta in sheep in New Zealand

AIM: To establish the efficacy of oral formulations of ivermectin and moxidectin against naturally acquired abomasal nematode infections on a North Island sheep farm. METHODS: Two controlled slaughter trials were undertaken. In the first, 30 sheep on pasture were randomly allocated on the basis of faecal egg count to 1 of 3 groups, comprising an untreated control group and 2 treatment groups. One treatment group was given a single oral dose of ivermectin and the other a single oral dose of moxidectin, both at the manufacturer's recommended dose rates of 0.2 mg/kg liveweight. Six days after treatment, all animals were slaughtered and their abomasa recovered for worm counting. The second trial, which involved 47 animals, was essentially the same as the first except that, as well as involving the slaughter of 30 sheep from all 3 groups, 6 days after treatment, it also included a further 8 untreated control animals and 9 moxidectin treated animals which were slaughtered 27 days after treatment. RESULTS: At 6 days after treatment, moxidectin was highly effective against all 3 of the abomasal nematodes present. While ivermectin was similarly effective against Trichostrongylus axei 6 days after treatment, it was not effective against either Ostertagia circumcinta or Haemonchus contortus, against which average efficacies of only 63.6% and 61.6%, respectively, were recorded. At 27 days after treatment, moxidectin, was also highly effective against T. axei (97.3% reduction) but not against either H. contortus (71.4% reduction) or O. circumcinta (61.0% reduction). CONCLUSIONS: These results provide the first record of macrocyclic lactone resistance in H. contortus in sheep or in any other host in New Zealand, and the first case where such resistance has been exhibited in more than one parasite species at a time. Although the therapeutic efficacy of moxidectin was high against these resistant H. contortus and O. circumcincta strains, resistance to moxidectin was indicated by its diminished prophylactic activity against them. It is suggested that this reduction in the prophylactic activity of moxidectin is also likely to reduce its apparent current high therapeutic efficacy. CLINICAL RELEVANCE: As well as providing further evidence that it can no longer be automatically assumed that macrocylic lactone anthelmintics will be effective on sheep farms in this country, these findings also present a warning that increasingly complex parasite control options may have to be faced in the future.     

An evaluation of an oral formulation of moxidectin against selected anthelmintic-resistant and -susceptible strains of nematodes in lambs

The efficacy of an oral formulation of the newly developed parasiticide, moxidectin, was tested against benzimidazole-resistant Haemonchus contortus, Trichostrongylus colubriformis, and Nematodirus spathiger, levamisole-resistant Ostertagia circumcincta, and susceptible Cooperia curticei infections in weaned lambs. Thirty-two lambs were experimentally infected with mixed doses of the above strains of nematodes. They were allocated into four treatment groups by stratified randomisation using liveweights and faecal egg counts 28 days later. One group received moxidectin at 0.2 mg/kg liveweight, one group oxfendazole at 4.5 mg/kg liveweight, one group levamisole at 7.5 mg/kg liveweight and the last group remained untreated as the control. Worm burdens in the lambs at slaughter 10 days after oral treatment confirmed the resistance status of the nematode strains used, and showed that moxidectin had a greater than 99.9% efficacy (p<0.01) against all of them. No adverse effects due to treatment with moxidectin were observed in any of the animals.     

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.     

Assessing resistance of ivermectin and moxidectin against nematodes in cattle naturally infected using three different methodologies

The objective of this study was to evaluate the accuracy of the faecal egg count reduction test (FECRT) and the faecal egg count efficacy test (FECET) to assess the resistance status of ivermectin (630 μg/kg) and moxidectin (200 μg/kg), using the controlled efficacy test as a reference, and whether the results of the EPG are equivalent to the efficacy results from the parasitological necropsies. Two experiments were conducted. The results demonstrate that it was not possible to demonstrate that the EPG values were equivalent with the ivermectin and moxidectin efficacy obtained by parasitological necropsies, mainly if the phenomenon of parasites resistance is not advanced in a determined field population. Maybe the FECET technique would be possibly better than the FECRT. The high anthelmintic efficacy of 200 μg/kg moxidectin, in naturally infected cattle, against field population of nematodes that are resistant to 630 μg/kg ivermectin, was observed in this study.     

Comparative long-term efficacy of ivermectin and moxidectin over winter in Canadian horses treated at removal from pastures for winter housing

The impact of a late fall treatment on the spring rise of fecal egg counts was evaluated in a controlled study with Canadian horses treated with 2 different dewormers immediately after removal from pasture for winter housing. The horses were stabled until the end of the trial period. Seventeen weanlings, 20 yearlings, and 15 2-year-old horses located in Ontario, which were presumed to be naturally infected with cyathostomins after pasture grazing, were randomly allocated to either a group treated with 0.4 mg/kg of moxidectin and 2.5 mg/kg of praziquantel or a group treated with 0.2 mg/kg of ivermectin and 1.5 mg/kg of praziquantel. Three weeks after treatment, all strongyle fecal egg counts were reduced to zero for both treatment groups. However, at 5 months post-treatment, mean geometric fecal egg counts were statistically higher for the yearlings and 2-year-old horses treated with ivermectin than for the yearlings and 2-year-old horses treated with moxidectin (P < 0.0001).     

THIABENDAZOLE RESISTANCE IN FIELD POPULATIONS OF HAEMONCHUS CONTORTUS

Six populations of H. contortus were selected for a study of thiabendazole resistance from a collection of 40 populations made during a survey of the efficiency of thiabendazole on the Northern Tablelands of New South Wales. Based on survey results, 3 of these populations were considered susceptible and the remaining 3 were considered resistant. However, when these populations were compared with a known susceptible strain on the ability of their eggs to hatch in a solution containing thiabendazole and 0.1% NaCl all 6 had significantly greater LC50's. The resistance ratios of the LC50 for each of the 6 populations to that of the known susceptible strain were 5.1, 4.3, 3.2, 3.1, 2.3, and 1.6 respectively. Following dosing of their host with 44 mg/kg thiabendazole the resistance ratios of the survivors increased to 5.4, 5.1, 4.7, 4.4, 3.1 and 2.4. Eggs produced by the F1 generation of the worms surviving 44 mg/kg thiabendazole did not revert back to the lower LC50's of the unselected parents. Rather the LC50 remained at a level near that of a known highly resistant strain of H. contortus.     

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.