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Albendazole (ABZ) was administered intraruminally at 4.75 mg/kg to sheep fitted with a permanent bile-duct cannula to determine if its metabolites might contribute to its flukicidal action. ABZ metabolism was consistent with first-pass clearance by the liver, resulting in ABZ sulphoxide (ABZ-SO) and ABZ sulphone (ABZ-SO2) being present in plasma at maximum concentrations (mean Cmax +/- SD) of 2.0 +/- 0.2 micrograms/ml and 0.4 +/- 0.1 micrograms/ml after 8 +/- 3 h and 24 +/- 5 h, respectively. ABZ-SO, but more particularly ABZ-SO2, appeared to bind to plasma proteins but their clearance rates from plasma were similar. Biliary ABZ metabolites were mainly unconjugated ABZ-SO and 2OH-ABZ-SO (8.0% dose) or conjugated glucuronide and sulphate esters (6.3% dose) mainly of 2OH-ABZ-SO and 2OH-ABZ-SO2. The concentration of the major biliary metabolite, unconjugated ABZ-SO, followed a similar time profile to that of ABZ-SO in plasma except that Cmax was much higher (6.2 +/- 2.2 micrograms/ml). Intraruminal administration of ABZ reduced bile flow rate by 30% which may be attributable to an inhibitory effect of ABZ on microtubule formation in hepatic secretory cells. It is suggested that ABZ is sequestered in the liver. This is unlikely to contribute to its flukicidal action, which is probably attributable to ingestion of ABZ-SO from bile and blood by the fluke.

Anthelmintic effects of oxfendazole continuously released at 0:17, 0.28 and 0.47 mg/kg/day from intraruminal capsules were assessed in groups of sheep artificially infected with Ostertagia circumcincta. Removal of worms was directly related to both release rate and plasma concentrations of drug. At the highest level, worm burdens were removed within seven days of administration and anthelmintic efficiency was 99.9 +/- 0.04, 99.3 +/- 0.5 and 98.9 +/- 0.7 per cent against adult worms, developing fourth stage and early fourth stage larvae respectively. In a field experiment, comparisons were made of the parasitological and animal production differences between groups of weaned lambs which were given no treatment, a single oral dose of 5 mg/kg oxfendazole and capsules releasing either 0.24 or 0.48 mg/kg oxfendazole daily. By four days after administration of capsules worm egg counts were reduced and remained below detectable levels for up to 86 days. Worm counts from 'tracer' and flock sheep showed a reduction in worm numbers, especially for Trichostrongylus spp. Compared with untreated controls, live weight gain and fleece weight of sheep given capsules releasing 0.48 mg/kg oxfendazole daily was increased.

Disphenol was administered to sheep infected with Haemonchus contortus in order to prevent the development of populations of adult worms, and studies were made of the pathogenicity of the arrested fourth-stage larvae which remained. The treated sheep showed elevated plasma pepsinogen and abomasal pH, predominantly negative dry-matter balance, and evidence of greater fluid loss, including plasma, into the gastro-intestinal tract. It was concluded that arrested larvae may cause damage to the abomasal mucosa.

Three mean particle sizes of oxfendazole raw material (1.65 micron, lot A; 3.2 micron, 10t B; 12.0 micron, lot C) were prepared and identically formulated as corresponding (A, B, and C) suspensions at 2.26% (W/V) concentration. Studies involving microscopic examination, scanning electron microscope analysis, particle size distribution, and surface area measurement were carried out on raw materials. In vitro dissolution profiles were obtained for the suspensions. A comparative bioavailability study of these 3 suspensions was performed in 12 sheep with each sheep given each formulation in a Latin square crossover study design; oxfendazole was dosed at rate of 5 mg/kg of body weight. Plasma-value measurements were made followed by an analysis of various bioavailability studies. Plasma area values indicated that suspension C (dw = 12.0 micron) was significantly (P less than 0.05) less bioavailable than was suspension A (dw = 1.65 micron); there was no difference between suspension A and suspension B. Significant differences were not seen in biological half-life and maximum plasma concentrations. The term dw refers to that particle diameter (determined by Coulter counting) at which 50% of the oxfendazole mass was in the form of particles having a lesser diameter and 50% was in the form of particles having a greater diameter. In a separate study involving 20 Merino weaner sheep infected with benzimidazole-resistant Haemonchus contortus larvae, oxfendazole's anthelmintic efficacy was demonstrated in the 2.26% suspension dosage form (90% particles less than 10 micron) at a dosing rate of 5 mg/kg. A correlation was found between its anthelmintic activity and plasma area values when compared in individual sheep. Data demonstrated that substantial differences in particle size distribution of oxfendazole could influence its dissolution rate, plasma concentrations, and absorption characteristics, thus indicating that oxfendazole's absorption could be dissolution-rate limited.

The binding of tritiated benzimidazoles (BZs)-albendazole, parbendazole, oxibendazole, mebendazole, oxfendazole and fenbendazole-to crude tubulin extracts from BZ-susceptible and -resistant Haemonchus contortus has been examined. For all BZs, the binding was substantially lower in the resistant isolate. The extent of this reduction was dependent on the structure of the BZ, with mebendazole demonstrating superior binding to the resistant isolate than the other BZs. Enrichment of the crude tubulin extract using polylysine-linked agarose demonstrated that for both isolates more than 85% of the observed binding was to protein eluted in the tubulin-containing fraction. Based on biochemical kinetics, the change in tubulin associated with resistance is reduced capacity in resistant tubulin to bind BZ with little or no reduction in the association constant of the BZ-tubulin complex. Comparative egg hatch assay demonstrated a similar structural specificity with the resistance factor of mebendazole observed to be lower than that of albendazole, parbendazole, oxibendazole and thiabendazole. The results of both studies support the hypothesis that BZ resistance is due to a change in tubulin and that this change is dependent on the structure of the BZ.

Fenbendazole (FBZ) and thiabendazole (TBZ) were administered intraruminally with a single dose of an indigestible marker, chromium ethylenediaminetetra-acetate (Cr-EDTA), to cattle fitted with gastrointestinal cannulae. The amounts of anthelmintic leaving the rumen, abomasum and terminal ileum in digesta were derived by compartmental analysis of Cr-EDTA concentrations and integration of benzimidazole concentrations. TBZ was absorbed much more rapidly from the rumen than FBZ and only about 12% of the dose left the rumen in digesta compared with 30% of the FBZ. Approximately 10% and 8% of the TBZ dose appeared at the pylorus and terminal ileum, respectively. Of the above amounts, 9% in the abomasum and practically 100% in the ileum was present as 5-OH-TBZ, indicating that metabolites of absorbed TBZ were recycled to the gastrointestinal tract. Twenty-eight percent and 52% of the FBZ appeared at the pylorus and terminal ileum, respectively, indicating a substantial recycling of absorbed drug to the small intestine. It is suggested that biliary secretion of both TBZ and FBZ and their metabolites may contribute to this recycling. Maximal concentrations of TBZ occurred in plasma in 4 h compared with about 24 h for FBZ. TBZ and metabolites were excreted in urine much more rapidly than were FBZ and metabolites. In plasma and in each of the gastrointestinal compartments, FBZ persisted much longer than did TBZ. It was concluded that slower absorption and excretion and more extensive recycling to the gastrointestinal tract of FBZ, than of TBZ, contribute markedly to its greater potency against helminths.

The ability of parbendazole (PBZ) to potentiate co-administered oxfendazole (OFZ) was investigated. Administration of a range (1.35-36.0 mg/kg) of doses of PBZ with 4.53 mg OFZ/kg demonstrated that significant potentiation occurred at 4.5 mg PBZ/kg. At 4.5 mg PBZ/kg, the area under the plasma OFZ concentration curve was about twice that obtained from oral administration of OFZ alone. When tested against benzimidazole-resistant Haemonchus contortus and Trichostrongylus colubriformis, the mixture of 4.5 mg PBZ + 4.53 mg OFZ/kg was significantly more effective than 4.53 mg OFZ/kg alone, and PBZ alone showed no activity against these resistant nematodes. The demonstration of PBZ-OFZ potentiation has indicated a means of obtaining a more effective use of currently available anthelmintics in the treatment of helminthiasis.

Tubulin was estimated to account for 16.3% and 0.25% of protein in rat brain and Nippostrongylus brasiliensis supernatants, respectively. Tubulin from N. brasiliensis and rat brain have been partially purified using polylysine agarose chromatography and high performance liquid chromatography on a gel permeation column. Western blots with alpha- and beta-tubulin monoclonal antibodies confirmed the presence of tubulin in different fractions. The mobility of N. brasiliensis tubulin on sodium dodecyl sulfate-polyacrylamide gel electrophoresis was similar to that of rat brain tubulin. The isoelectric range for N. brasiliensis alpha- and beta-tubulin isoforms was pH 5.4-4.8 and pH 4.8-4.7, respectively. However, for rat brain the corresponding ranges were pH 5.4-4.9 and pH 5.0-4.6, respectively. Western blots with anti-tubulin monoclonal antibodies revealed 8 isoforms of alpha-tubulin and 3 isoforms of beta-tubulin for N. brasiliensis and 14-15 and 7-8 isoforms for rat brain alpha- and beta-tubulins, respectively. Different peptide maps were obtained for N. brasiliensis tubulin compared with rat brain tubulin.

The Nippostrongylus brasiliensis-rat model was used to determine whether iron and protein deficiency, which are commonly associated with parasitic infections, affected the pharmacokinetic behaviour of fenbendazole as measured by plasma concentrations and uptake by worms. Plasma 14C concentrations after [14C] fenbendazole administration were higher in iron and protein-deficient rats than in sufficient rats. However, the uptake of 14C by N. brasiliensis in iron and protein-deficient rats was significantly less than in worms from diet-sufficient rats. The reduced anthelmintic uptake by worms in protein and iron-deficient hosts may account, in part, for reduced anthelmintic efficacy under these circumstances. These findings are relevant to understanding variations in response to chemotherapy in populations of parasitised hosts containing malnourished individuals.

Praziquantel (PZ) at concentrations down to 5 x 10(-8) M induced a rapid contraction of Hymenolepis diminuta musculature. This effect was accompanied by a strong inhibition of 45Ca2+ incorporation which showed some dependence on Ca2+ concentration. Ca2+ efflux experiments showed that PZ markedly stimulated the release of Ca2+ from tapeworms preloaded with 45Ca2+, with the effluxed Ca2+ being derived from a small fast pool and a larger slow pool. This stimulatory effect appeared., like PZ-induced muscle contraction, to be independent of external Ca2+. By carrying out 45Ca2+ exchange experiments under near equilibrium conditions and atomic absorption spectroscopy it could be demonstrated that PZ resulted in a net excretion of endogenous Ca2+. In PZ-induced contracted worms adenylate nucleotide levels and the adenylate energy charge were not significantly different from those of untreated control worms. Also, PZ had no effect on Ca2+-stimulated ATPase activity of the tapeworm's tegumental brush border. Nor did the drug alter the activities of Ca2+-ATPases in whole homogenates of worms or mitochondria, microsomal or soluble fractions. Although the mechanism of PZ-induced changes in Ca2+ transport was not elucidated, it is suggested that the sustained release of endogenous Ca2+ may affect the sequence of excitation-contraction coupling and that such interference may cause the observed massive contraction of the tapeworm's musculature.

This experiment was designed to study, over a 5-year-period, the effect of different frequencies of treatment with three different anthelmintic groups, namely, benzimidazoles, levamisole and ivermectin, and different frequencies of alternation between them, on existing levels of anthelmintic resistance in the nematode parasites Haemonchus contortus and Trichostrongylus colubriformis of grazing sheep. No evidence of ivermectin resistance emerged, even in suppressively treated groups. Likewise, H. contortus failed to develop resistance to levamisole under a similar selection regimen. Thiabendazole was shown to select positively against levamisole resistance in T. colubriformis resulting in significantly greater susceptibility to this drug than for the natural reversion which occurred in the untreated control. There was no evidence that an anthelmintic treatment combined with a movement of sheep to pastures of low infectivity selected more rapidly for resistance than where the same number of treatments were given to set-stocked sheep. Rotation between anthelmintic groups at yearly intervals appeared to be more beneficial in delaying resistance than rotation of drugs with each treatment.

To investigate whether the disposition of triclabendazole (TCBZ) and its metabolites in blood or bile influenced its flukicidal potency, TCBZ was administered intraruminally at 10 mg kg-1 to sheep surgically fitted with a permanent re-entrant bile duct cannula. The profiles of TCBZ metabolites in peripheral plasma and bile were determined using high performance liquid chromatography. In plasma, only TCBZ sulphoxide (TCBZ-SO) and TCBZ sulphone were present and reached their maximum concentrations (greater than 13 micrograms ml-1) at 18 and 36 h, respectively, after administration. TCBZ metabolites were specifically bound to plasma albumin, which is believed to exert a major influence on the duration of plasma TCBZ metabolite concentrations and consequent exposure of liver fluke. In bile, the major TCBZ metabolites were hydroxylated in the 4' position and secreted predominantly as sulphate esters with lesser proportions as glucuronide conjugates. The major biliary metabolite was conjugated hydroxy TCBZ-SO which reached a maximum concentration in excess of 40 micrograms ml-1 and contributed almost half the total conjugated metabolites. The major free biliary metabolite was TCBZ-SO. Of the administered TCBZ dose, 9.7% was secreted as free metabolites in bile whereas 35.8% was secreted as conjugated metabolites. Approximately 6.5% of the dose was excreted in urine.

Direct intraabomasal oxfendazole (OFZ) administration resulted in the peak plasma OFZ concentration occurring sooner and the area under the plasma OFZ concentration curve being reduced when compared with intraruminal administration. Glucose given directly into the abomasum of fistulated sheep caused a substantially greater elevation of plasma glucose levels than did direct administration into the rumen. This difference was subsequently used to indicate rumen bypass, by oesophageal groove closure, after oral dosing with an OFZ formulation to which glucose had been added. When 17 penned sheep were drenched with OFZ containing added glucose, elevated plasma glucose levels indicated substantial rumen bypass in six of them and was negatively correlated with time to peak plasma OFZ concentration, area under the plasma OFZ curve and efficacy against thiabendazole resistant Haemonchus contortus. Among 60 grazing sheep there were indications of some degree of oesophageal groove closure in 42 per cent of them following drenching with OFZ and in these animals there was a significant reduction in OFZ efficiency as measured by faecal worm egg counts.

The pharmacokinetics of ivermectin in plasma following intravenous, intra-abomasal, and intraruminal administration to sheep was determined. When given intravenously, ivermectin was very slowly eliminated with a terminal half-life of 178 h and a volume of distribution at steady state of 5.3 l/kg indicating sequestration in a temporary depot. Intra-abomasal administration resulted in rapid absorption, a peak plasma concentration of 60.6 ng/ml at 4.4 h, and 100% bioavailability. However, intraruminal administration produced a much lower peak concentration (17.6 ng/ml at 23.5 h) and bioavailability (25.1%). A subsequent in vitro study indicated that ivermectin may be rapidly metabolized in the rumen.

Peritoneal exudate cells from mice infected with Schistosoma mansoni (S-PEC) can kill a small proportion of schistosomula in vitro in the presence of immune serum. S-PEC produce a low level of respiratory burst. However, schistosomula mortality in their presence is not reduced when exogenous antioxidants are added, suggesting that with S-PEC, oxidative killing may not be important. Hydrogen peroxide (H2O2) and superoxide production by S-PEC, and cells from Bacillus Calmette-Guerin (BCG) and thioglycollate (THGL) injected mice, nonspecifically stimulated with opsonized zymosan, were measured. Levels of H2O2 produced by S-PEC were significantly lower than BCG or THGL PEC, and were below the threshold for schistosomula killing. This correlated with lower levels of cell-mediated killing of schistosomula in vitro by S-PEC than by BCG-PEC. Superoxide levels, however, were similar between the 3 cell populations. It therefore appears that the efficiency of PEC to kill schistosomules in vitro correlates with H2O2 rather than superoxide levels. It was found that there was a sharp concentration threshold in H2O2 mediated killing of schistosomula. A depression in the levels of H2O2 produced may be a mechanism by which the parasite can partially evade the host immune system.

Benzimidazole treatment produced greater effects on microtubule-dependent acetylcholinesterase secretion, the presence of microtubules in intestinal cells, and colchicine binding in susceptible compared with benzimidazole-resistant Trichostrongylus colubriformis. In addition, the binding of benzimidazoles was markedly reduced in preparations from the latter strain, indicating that the mechanism of resistance to benzimidazoles in this nematode involves a reduced affinity of tubulin for benzimidazoles.

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.

Anthelmintic control of Ostertagia ostertagi in cattle presents some special problems because the arrested larval stage (hypobiotic EL4) tolerates all of the older anthelmintics. The only anthelmintics on the North American market that are effective against this stage as well as the adult and developing stages are ivermectin and fenbendazole. In addition to these, the newer broad-spectrum benzimidazoles and probenzimidazoles, albendazole, febantel, netobimin and oxfendazole, are effective and available in other countries. These anthelmintics can be used for prophylaxis of Type II ostertagiasis. The older anthelmintics, levamisole, morantel tartrate, thiabendazole, coumaphos, haloxon and phenothiazine, are effective against the adults and to some extent the developing stages of O. ostertagi so that they can be used to treat Type I ostertagiasis. They can also be used to prevent incoming larvae from establishing if they are administered continuously over a long period of time. This is possible with long term in-feed administration or by the use of the morantel slow release bolus. In cooler temperature regions, where cattle are housed over the winter, this bolus is given at turnout to remove any parasites in the animals and to kill incoming larvae for 60-90 days. This can prevent the build up of significant infective larvae on pasture so that very few arrested L4 larvae accumulate in the summer/autumn, effectively preventing Type II ostertagiasis from occurring later. The use of ivermectin and the newer benzimidazoles in intermittent or slow release devices should prove highly effective in the control of Type I and II ostertagiasis, as well as of subclinical ostertagiasis. To achieve maximum economic benefit, the use of anthelmintics should be based on sound epidemiological considerations, so that stock are not rapidly reinfected after treatment.

Acetate, propionate, ethanol and propanol were the predominant end-products released during incubation of a thiabendazole resistant and a susceptible strain of Trichostrongylus colubriformis. The parasites in all the incubations appeared to be deficient in reducing equivalents if the end-products arose from the classical catabolic pathway through fumarate reductase (EC 1.3.1.6). Possible alternative pathways for accounting for redox balance, including beta-oxidation, the pentose phosphate pathway and amino acid metabolism were investigated. Palmitate was oxidised aerobically. Radiolabelled tricarboxylic acid cycle intermediates, citrate and alpha-ketoglutarate, were decarboxylated to 14CO2 indicating that at least a partial tricarboxylic acid cycle to succinyl-CoA via alpha-ketoglutarate operates both anaerobically and aerobically in T. colubriformis. These data and the pattern of end-products suggest the presence of two pathways to propanol and propionate either through fumarate reduction or alpha-ketoglutarate oxidation. T. colubriformis may apportion carbon flow through these pathways to maintain a stable redox ratio. Similar calculations on previously reported data indicate that both pathways may also operate in Haemonchus contortus. Exposure of resistant T. colubriformis to thiabendazole under anaerobic conditions caused an increased accumulation of end-products, especially propanol, in the incubation medium. The alpha-ketoglutarate pathway may lower the dependence of the parasite on the fumarate reductase route which is sensitive to thiabendazole. The operation of the alpha-ketoglutarate pathway, with propanol as an end-product, may provide a mechanism for regulating redox balance in trichostrongylidae.

Comparisons were made of the relative efficacy of ozfendazole (OFZ), administered to sheep at 5 mg/kg either as an oral drench, single intravenous injection or 12 and 24 divided intravenous injections over 24 and 48 hours, against benzimidazole-resistant Haemonchus contortus and Trichostrongylus colubriformis. A single intravenous injection was at least equally potent as the oral drench whilst the divided dose intravenous regimes significantly increased OFZ efficacy against both parasite species. These findings demonstrate that (i) absorbed drug is important for the efficacy of OFZ against nematodes in the abomasum and small intestine and may be more important than unabsorbed drug passing down the gastrointestinal tract, and (ii) the maintenance of plasma OFZ levels of approximately 2 micrograms/ml by divided dose regime increased efficacy compared with that achieved with the same total dose given as a single administration.

Peritoneal exudate cells from mice infected with Schistosoma mansoni (S-PEC) can kill schistosomula in vitro in the presence of immune serum. S-PEC produce a low level of respiratory burst, and schistosomula mortality in their presence is not reduced when exogenous antioxidants are added, suggesting that with S-PEC, oxidative killing is not important. Hydrogen peroxide (H2O2) and superoxide production by S-PEC, and cells from BCG and thioglycollate (THGL) injected non-infected mice, non-specifically stimulated with opsonized zymosan, were measured. Levels of H2O2 produced by S-PEC were significantly lower than BCG or THGL PEC, and were below the H2O2 threshold for schistosomula killing. This resulted in lower levels of cell-mediated killing of schistosomula in vitro by S-PEC than by BCG or THGL PEC. Superoxide levels, however, were similar between the three cell populations. The efficiency of PEC to kill schistosomules in vitro correlated with H2O2 rather than superoxide levels. The lower tolerance of schistosomula, compared to adult S. mansoni to GSH depleting agents increases their sensitivity to oxidative attack and resulted in higher levels of cell-mediated killing in vitro.

The correlation between the inhibition of hatching of Haemonchus contortus eggs and inhibition of mammalian tubulin polymerisation by benzimidazole carbamates has been investigated. The hatching process was observed to be independent of the biomass (eggs plus debris) over a 6-fold range and the early (E1-E3) stages of egg development, but was dependent on the concentration of co-solvent (DMSO) and time of incubation. Benzimidazole carbamates with strong inhibitory activity against mammalian tubulin were potent inhibitors of egg hatch, while non-inhibitors failed to prevent hatching. It is postulated that the primary mode of action of these drugs on nematode eggs is the inhibition of microtubule-dependent processes within the developing egg. The implications and limitations of this correlation are discussed.

The tubulins of Brugia malayi and B. pahangi were similar with respect to concentration (mg tubulin per mg soluble protein), electrophoretic and isoelectric mobility, reaction in Western blots with anti-tubulin monoclonal antibodies, and isoform patterns. Tubulin was estimated to account for 2.8% and 2.9% of soluble protein in B. malayi and B. pahangi extracts, respectively. Tubulins from Brugia nematodes have been partially purified by polylysine agarose chromatography and with taxol. Western blots with alpha- and beta-tubulin monoclonal antibodies confirmed the presence of tubulin. The mobility of Brugia tubulins on sodium dodecyl sulfate polyacrylamide gel electrophoresis was very similar to that of N. brasiliensis and rat brain tubulins. The isoelectric range for Brugia alpha- and beta-tubulin isoforms was pH 5.4-4.7. Western blots with anti-tubulin monoclonal antibodies revealed 4-5 isoforms of alpha-tubulin and 4-5 isoforms of beta-tubulin for Brugia nematodes.

Antiparasitic drugs must be conducted to the parasite by the host and are therefore subject to physiological and biochemical processes in the host. Usually the efficacy of an antiparasitic drug will depend on a toxic concentration being presented to the parasite for sufficient time to lead to irreversible damage. Because many drugs are, in part, absorbed and transported to the site of the parasite by the circulatory system the area under the plasma concentration curve (AUC) may reflect availability of drug to the parasite and likely efficacy. A number of host physiological factors affect the AUC. Many anthelmintics are given orally as solids. Some absorption occurs in the rumen of ruminants, but many heterocyclic compounds such as the benzimidazoles require the low pH of the abomasum or gastric stomach to render them soluble. Certain disease states, including gastrointestinal parasitism, can cause the gastric pH to rise. This may in turn reduce solubility and absorption with resultant faster rate of excretion, particularly when accompanied by diarrhoea, and a reduced AUC. Once the anthelmintic has been absorbed, after oral or systemic administration, it is usually rapidly transported to the liver. The liver and adipose tissue may store the drug, releasing it over a period to produce a sustained effect as occurs with ivermectin, or it may rapidly metabolise it. A few anthelmintics, such as febantel, probably need to be metabolised in order to become active. However, more frequently the liver is involved in oxidation or reduction, followed by conjugation with sulfate, glucuronide or glutathione to render the drug more polar, to increase its molecular weight, inactivate it and facilitate its excretion. The rate of metabolism has been found to vary considerably between species and thus different dose rates and treatment are often required to achieve adequate antiparasite activity, with species such as deer, cattle and probably goats metabolising some anthelmintics faster than sheep. Some interesting possibilities for altering the absorption and metabolism of anthelmintics by the host may allow improved efficacy and reliability of antiparasite activity without necessarily increasing the dose rate of anthelmintic.