Ivermectin disposition kinetics after subcutaneous and intramuscular administration of an oil-based formulation to cattle.

Slight differences in formulation may change the plasma kinetics and ecto-endoparasiticide activity of endectocide compounds. This work reports on the disposition kinetics and plasma availability of ivermectin (IVM) after subcutaneous (SC) and intramuscular (IM) administration as an oil-based formulation to cattle. Parasite-free Aberdeen Angus calves (n = 24; 240-280 kg) were divided into three groups (n = 8) and treated (200 microg/kg) with either an IVM oil-based pharmaceutical preparation (IVM-TEST formulation) (Bayer Argentina S.A.) given by subcutaneous (Group A) and intramuscular (Group B) injections or the IVM-CONTROL (non-aqueous formulation) (Ivomec, MSD Agvet) subcutaneously administered (Group C). Blood samples were taken over 35 days post-treatment and the recovered plasma was extracted and analyzed by HPLC using fluorescence detection. IVM was detected in plasma between 12 h and 35 days post-administration of IVM-TEST (SC and IM injections) and IVM-CONTROL formulations. Prolonged IVM absorption half-life (p < 0.05) and delayed peak plasma concentration (p < 0.001) were obtained following the SC administration of the IVM-TEST compared to the IVM-CONTROL formulation. No differences in total plasma availability were observed among treatments. However, the plasma residence time and elimination half-life of IVM were significantly longer after injection of the IVM-TEST formulation. IVM plasma concentrations were above 0.5 ng/ml for 20.6 (CONTROL) and 27.5 days (IVM-TEST SC), respectively (p < 0.05). The modified kinetic behaviour of IVM obtained after the administration of the novel oil-based formulation examined in this trial, compared to the standard preparation, may positively impact on its strategic use in cattle.     

Pharmacokinetic evaluation of four ivermectin generic formulations in calves

The plasma concentration profiles of four randomly chosen ivermectin (IVM) generic formulations (IVM G1-G4) were compared after their subcutaneous (SC) administration to healthy calves. The disposition of other avermectin-type endectocide compounds, doramectin (DRM) and abamectin (ABM), was also assessed in the same pharmacokinetic trial. Forty-two parasite-free Aberdeen Angus male calves were randomly allocated into six treatment groups. Animals in each group (n = 7) received SC treatment (200 microg/kg) with one of the commercially available endectocide formulation used in the trial. Blood samples were taken into heparinised vacutainer tubes from the jugular vein prior to and up to 35 days post-treatment. The recovered plasma was analysed by HPLC with fluorescence detection. Large kinetic differences were observed among the DRM, ABM and IVM formulations under evaluation. The DRM plasma concentration profiles were higher than those measured for ABM and all the IVM generic formulations. The higher and sustained plasma concentrations of DRM accounted for greater area under concentration-time curve (AUC) and longer mean residence time (MRT) values compared to those obtained for both ABM and the IVM generic preparations. The pattern of IVM absorption from the site of subcutaneous administration showed differences among the generic formulations under evaluation. The IVM G2 preparation showed higher peak plasma concentration and AUC values (P < 0.05) compared to those obtained after the administration of the IVM G1 formulation. Longer (P < 0.05) MRT values were obtained after the administration of the IVM G3 compared to other IVM generic preparations. The kinetic behaviour of ABM did not show significant differences with that described for most of the IVM formulations. This study demonstrates that major differences on drug kinetic behaviour may be observed when using different endectocide injectable formulations in cattle.     

Comparative plasma disposition kinetics of ivermectin, moxidectin and doramectin in cattle

The persistence of the broad-spectrum antiparasitic activity of endectocide compounds relies on their disposition kinetics and pattern of plasma/tissues exchange in the host. This study evaluates the comparative plasma disposition kinetics of ivermectin (IVM), moxidectin (MXD) and doramectin (DRM) in cattle treated with commercially available injectable formulations. Twelve (12) parasite-free male Hereford calves (180–210 kg) grazing on pasture were allocated into three groups of four animals each. Animals in each group received either IVM (Ivomec 1%, MSD AGVET, Rahway, NJ, USA), MXD (Cydectin 1%, American Cyanamid, Wayne, NJ, USA) or DRM (Dectomax 1%, Pfizer Inc., New York, NY, USA) by subcutaneous injection at a dose of 200 μg/kg. Jugular blood samples were collected from 1 h up to 80 days post-treatment, and plasma extracted, derivatized and analysed by high performance liquid chromatography (HPLC) using fluorescence detection. The parent molecules were detected in plasma between 1 h and either 70 (DRM) or 80 (IVM and MXD) days post-treatment. The absorption of MXD from the site of injection was significantly faster (absorption half-life (t_½ab) = 1.32 h) than those of IVM (t_½ab= 39.2 h) and DRM (t_½ab= 56.4 h). MXD peak plasma concentration (C_max) was reached significantly earlier (8.00 h) compared to those of IVM and DRM (4–6 days post-treatment). There were no differences on C_max values; the area under the concentration–time curve (AUC) was higher for IVM (459 ng.d/mL) and DRM (627 ng.d/mL) compared to that of MXD (217 ng.d/mL). The mean plasma residence time was longer for MXD (14.6 d) compared to IVM (7.35 d) and DRM (9.09 d). Unidentified metabolites were detected in plasma; they accounted for 5.75% (DRM), 8.50% (IVM) and 13.8% (MXD) of the total amount of their respective parent drugs recovered in plasma. The comparative plasma disposition kinetics of IVM, MXD and DRM in cattle, characterized over 80 days post-treatment under standardized experimental conditions, is reported for the first time.     

A comparative kinetic study of ivermectin and moxidectin in lactating camels (Camelus dromedarius).

The plasma and milk kinetics of ivermectin (IVM) and moxidectin (MXD) was evaluated in lactating camels treated subcutaneously (0.2 mg kg(-1)) with commercially available formulations for cattle. Blood and milk samples were taken concurrently at predetermined times from 12 h up to 60 days post-administration. No differences were observed between plasma and milk kinetics of IVM, while substantial differences were noted between plasma and milk profiles of MXD in that both the maximal concentration (Cmax) and the area under concentrations curves (AUC) were three to four-fold higher for milk than for plasma. The time (Tmax) to reach Cmax was significantly faster for MXD (1.0 day) than that for IVM (12.33 days). The Cmax and the AUC were significantly higher for MXD (Cmax = 8.33 ng ml(-1); AUC = 70.63 ng day ml(-1)) than for IVM (Cmax = 1.79 ng ml(-1); AUC = 30.12 ng day ml(-1)) respectively. Drug appearance in milk was also more rapid for MXD (Tmax = 3.66 days) compared to IVM (Tmax = 17.33 days). The extent of drug exchange from blood to milk, expressed by the AUCmilk/AUCplasma ratio, was more than three-fold greater for MXD (4.10) compared to that of IVM (1.26), which is consistent with the more lipophilic characteristic of MXD. However, the mean residence time (MRT) was similar in both plasma and milk for each drug.     

Enhanced plasma and target tissue availabilities of albendazole and albendazole sulphoxide in fasted calves: evaluation of different fasting intervals

The influence of different pre- and post-treatment fasting periods on the plasma availability and disposition kinetics of albendazole (ABZ) and its sulphoxide metabolite (ABZSO) in cattle was investigated. The effect of fasting on the distribution of ABZ and ABZSO to different target tissues/fluids was also characterised. In Experiment I, 35 parasite-free Holstein calves were divided into seven groups according to the following feeding conditions and treated intraruminally with ABZ (10 mg/kg): control group (fed ad libitum), 24 h fasting either prior to (24 h pre-) or post (24 h post-) treatment, 24 h fasting with either 6 (6 h pre + 18 h post) or 12 h (12 h pre + 12 h post-) of feed restriction prior to treatment, 12 h fasting either prior to (12 h pre-) or post (12 h post) treatment. In Experiment II, calves from the same pool of animals were subjected to a 24 h fasting period prior to the same ABZ treatment and killed (two animals) at either 24, 36 or 48 h post-administration to obtain samples of abomasal/intestinal mucosa and fluid contents, bile and lungs. Plasma (Experiment I) and tissues/fluids (Experiment II) samples were analysed by HPLC. All the fasting periods investigated induced marked changes to the plasma availability and disposition kinetics of the ABZSO metabolite. Enhanced plasma availability between 37 and 118%, delayed peak concentrations and extended mean residence times for ABZSO were observed in fasted compared to fed calves. The changes in plasma kinetics, reflecting an altered quantitative gastrointestinal absorption, were reflected in increased availability of ABZ and ABZSO in the target tissues/fluids of fasted calves. The availabilities of ABZ and ABZSO in the gastrointestinal mucosa and fluids in fasted calves were markedly greater than in those fed ad libitum.     

Comparative evaluation of two ivermectin injectable formulations against psoroptic mange in feedlot cattle

A study was carried out to compare the efficacy of two injectable formulations of ivermectin, Ivomec,(1) Merial (IVM reference) and Ivogell,(2) Intervet (IVM generic) in the treatment of psoroptic mange (Psoroptes ovis) in Charollais feedlot cattle. A total of 22 animals were ranked in order of the severity of mange and allocated to 11 replicates of 2 animals each. Within each replicate, one animal was randomly allocated to IVM reference product treatment (Group 1) and one to IVM generic (Group 2). Animals were treated on Day 0 and on Day 8 at the recommended dosage of 200 microg ivermectin/kg bodyweight. The pharmacokinetics profiles (pK) of both IVM formulations were evaluated in plasma samples taken from 6 cattle randomly chosen per group on Day 0, before treatment, and then at 6, 12, 24 hours and daily from Day 2 to Day 7 after the treatment on Day 0. Additionally, the severity of mange lesions was assessed and mites were counted in skin scrapings on Days 0, 8, 15 and 25. Animals were weighed on Day 0 and 25 and body weight and average daily gains (ADG) were evaluated. No statistical differences were found between the cattle of the two groups in any pK parameters, although the mean IVM plasma concentrations in cattle treated with the IVM reference product were consistently higher than those found in cattle treated with the generic compound. By Day 25, all animals in Group 1 had recovered clinically and parasitologically from psoroptic mange while cattle from Group 2 still had mange lesions and, in two animals, living mites were found in the skin scrapings; these differences were significant (P<0.001). The mean body weight of the two groups was significantly different on Day 25 (P<0.01) when animals in Group 1 weighed 20 kg more than those in Group 2. In conclusion, despite similarities in their pharmacokinetic profiles and formulations, the clinical efficacy of the two injectable formulations of IVM differed significantly in their therapeutic efficacy against psoroptic mange in feedlot cattle up to 25 days after treatment: this difference in response was reflected in an incomplete clinical and parasitological response in Group 2 and a slower growth rate.     

Assessment of the long‐acting ivermectin formulation in sheep: Further insight into potential pharmacokinetic interactions

The aim of the current study was to evaluate the in vivo pharmacokinetic of ivermectin (IVM) after the administration of a long‐acting (LA) formulation to sheep and its impact on potential drug‐drug interactions. The work included the evaluation of the comparative plasma profiles of IVM administered at a single therapeutic dose (200 μg/kg) and as LA formulation at 630 μg/kg. Additionally, IVM was measured in different gastrointestinal tissues at 15 days posttreatment with both IVM formulations. The impact of the long‐lasting and enhanced IVM exposure on the disposition kinetics of abamectin (ABM) was also assessed. Plasma (IVM and ABM) and gastrointestinal (IVM) concentrations were analyzed by HPLC with fluorescent detection. In plasma, the calculated C_max and AUC_0‐t values of the IVM‐LA formulation were 1.47‐ and 3.35‐fold higher compared with IVM 1% formulation, respectively. The T_1/2ab and T_max collected after administration of the LA formulation were 2‐ and 3.5‐fold longer than those observed after administration of IVM 1% formulation, respectively. Significantly higher IVM concentrations were measured in the intestine mucosal tissues and luminal contents with the LA formulation, and in the liver, the increase was 7‐fold higher than conventional formulation. There was no drug interaction between IVM and ABM after the single administration of ABM at 15 days post‐administration of the IVM LA formulation. The characterization of the kinetic behavior of the LA formulation to sheep and its potential influence on drug‐drug interactions is a further contribution to the field.     

Three treatments with ivermectin in year-long control of gastrointestinal nematode parasites of weaner-yearling beef cattle

Four groups of 17 crossbred beef weaners were used in an experiment which extended from 14 November 1985 to 8 October 1986 (328 days). All groups began grazing on separate, contaminated pastures at a stocking rate of 5.3 cattle ha-1 and the different treatments were: Group 1, ivermectin (IVM) injectable X 1 (200 micrograms kg-1) on 14 November only, with provision for individual salvage treatment; Group 2, IVM X 3 on 14 November, 4 February and 2 July; Group 3, IVM X 2 on 14 November and 2 July; Group 4, fenbendazole (FBZ) paste X 2 (5 mg kg-1) on 14 November and 2 July. Pairs of parasite-free tracer calves were grazed on all group pastures for 1 month at the beginning of the experiment (13 November-12 December and in spring (1 April-1 May). Yearling cattle from each group were randomly selected and removed from pasture during spring (n = 2 per group, 3 April) and at the end of the experiment (n = 3 per group, 8 October) for slaughter analysis of worm population characteristics and observation of gross pathology in the abomasum and intestinal tract. At monthly intervals, all cattle were weighed and fecal egg counts, pasture larval counts and plasma pepsinogen values were determined. The results of this investigation demonstrated that three IVM treatments of weaner-yearling beef cattle during year-long grazing, were more effective than a single IVM treatment or two treatments with IVM or FBZ in the enhancement of productivity and protection from the effects of infection with nematode parasites.     

Breed differences on the plasma availability of moxidectin administered pour-on to calves

The pharmacokinetic profile of avermectin and milbemycin compounds is affected by different drug- and host-related factors. This work reports the influence of cattle breeds on the plasma kinetics of moxidectin (MXD) after topical (pour-on) administration. Parasite-free Aberdeen Angus and Holstein calves were treated with a commercial MXD pour-on formulation at 500 microg/kg. Blood samples were collected over a period of 35 days post-treatment and the recovered plasma was analysed by high performance liquid chromatography using fluorescence detection. MXD was detected in plasma from two hours up to 35 days post-treatment in animals from both breeds. A slow MXD absorption and delayed peak plasma concentration were observed in Aberdeen Angus compared to Holstein calves. Significant lower systemic availability (expressed as AUC) (P<0.01) and peak plasma concentration (C(max)) (P<0.05) were also observed in Aberdeen Angus calves, although the plasma mean residence time (MRT) and elimination half-lives (T(1/2el)) of MXD in both breeds were similar. The pharmacokinetic differences observed between cattle breeds contribute to explain the variability in the pattern of clinical efficacy for pour-on administered endectocide compounds reported in different field trials.     

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.     

Comparative distribution of ivermectin and doramectin to parasite location tissues in cattle

Pharmacokinetic studies have been used traditionally to characterize drug concentration profiles achieved in the bloodstream. However, endectocide molecules exert their persistent and broad spectrum activity against parasites localized in many different tissues. The aim of this study was to compare the distribution of ivermectin (IVM) and doramectin (DRM) to different tissues in which parasites are found following subcutaneous administration to calves. Holstein calves weighing 120-140 kg were injected in the shoulder area with commercially available formulations of IVM (Ivomec 1% MSD AGVET, NJ, USA) (Group A) or DRM (Dectomax 1%, Pfizer, NY, USA) (Group B). Two treated calves were sacrificed at 1, 4, 8, 18, 28, 38, 48 or 58 days post-treatment. Plasma, abomasal and small intestinal fluids and mucosal tissues, bile, faeces, lung and skin samples were collected, extracted, derivatized and analyzed by high performance liquid chromatography (HPLC) with fluorescence detection to determine IVM and DRM concentrations. IVM and DRM were distributed to all the tissues and fluids analyzed. Concentrations >0.1 ng/ml (ng/g) were detected between 1 and 48 days post-treatment in all the tissues and fluids investigated. At 58 days post-treatment, IVM and DRM were detected only in bile and faeces, where large concentrations were excreted. Delayed Tmax values for DRM (4 days post-administration) compared to those for IVM (1 day) were observed in the different tissues and fluids. High IVM and DRM concentrations were measured in the most important target tissues, including skin. The highest IVM and DRM concentrations were measured in abomasal mucosa and lung tissue. Enhanced availabilities of both IVM (between 45 and 244%) and DRM (20-147%) were obtained in tissues compared to plasma. There was good correlation between concentration profiles of both compounds in plasma and target tissues (mucosal tissue, skin, and lung). Drug concentrations in target tissues remained above 1 ng/g for either 18 (IVM) or 38 (DRM) days post-treatment. The characterization of tissue distribution patterns contributes to our understanding of the basis for the broad-spectrum endectocide activity of avermectin-type compounds.     

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.     

The effects of body composition on the pharmacokinetics of subcutaneously injected ivermectin and moxidectin in pigs

Macrocyclic lactones are characterized by their long persistence in animals because of their extensive distribution into fat. This study examined the influence of body condition on the disposition of ivermectin (IVM) and moxidectin (MXD) in blood and fat following subcutaneous (s.c.) drug administration. 'Fat' and 'thin' lines of pigs were established using two different diets. All animals were then injected with either MXD or IVM at 300 microg/kg and blood samples were taken at regular intervals until slaughter. Two IVM-treated animals from each diet group were slaughtered at either 3 days or 3 weeks posttreatment. Two MXD-treated animals from each diet group were slaughtered at 3 days, 3, 6 or 9 weeks after treatment. Samples of backfat were taken from all animals at slaughter. Fluorescence HPLC was used to determine the concentrations of MXD or IVM in the plasma and fat samples. The plasma IVM concentration peaked more rapidly in the thin IVM treated pigs compared with the fat pigs. The concentration of IVM in backfat was significantly lower in the thin animals slaughtered 3 weeks after treatment. The MXD plasma concentration peaked within the first hour in both the thin and fat groups, but from 12 h posttreatment there was a higher MXD concentration in the plasma of the fat pigs resulting in MXD being detectable in these pigs for 28 days compared with only 17 days in the thin pigs. Despite this difference in plasma persistence no differences were seen in the MXD concentration of backfat between fat and thin animals. Body condition influenced the kinetic disposition of IVM and MXD following s.c. drug administration with both drugs being less persistent in thin compared with fat animals.     

The comparative serum disposition kinetics of subcutaneous administration of doramectin, ivermectin and moxidectin in the Australian Merino sheep

This study evaluates the comparative serum disposition kinetics of injectable formulations of doramectin (DRM), ivermectin (IVM) and moxidectin (MXD) in Australian Merino sheep. Thirty-six, 2-year-old sheep were allocated by weight into six groups of six animals. Animals in each group received 200 microg/kg of DRM, MXD, IVM or a combination of two of these drugs by subcutaneous (s.c.) injection. Blood was collected at designated intervals (between 1 h and 40 days after treatment) and the serum analysed by high performance liquid chromatography (HPLC) using fluorescence detection. The results indicated that MXD administration produced a significantly higher maximum serum concentration and a more rapid absorption as compared with DRM and IVM. MXD and DRM had a significantly larger area under the concentration vs. time curve (AUC) than IVM, suggesting a more persistent effect for the former two products in sheep. The AUC for DRM was significantly higher when administered alone as compared with that observed when given in combination with MXD or IVM, suggesting preferential elimination of DRM compared with IVM and MXD from concurrent s.c. administration.     

Comparative plasma dispositions of ivermectin and doramectin following subcutaneous and oral administration in dogs

This study evaluates the comparative plasma dispositions of ivermectin (IVM) and doramectin (DRM) following oral and subcutaneous administration (200 microg/kg) over a 40-day period in dogs. Twenty bitches were allocated by weight in to four groups (Groups I-IV) of five animals each. Animals in the first two groups (Groups I and II) received orally the injectable solutions of IVM and DRM, respectively, at the dose of 200 microg/kg bodyweight. The other two groups (Groups III and IV) received subcutaneously injectable solutions at the same dose rate. Blood samples were collected between 1h and 40 days after treatment and the plasma samples were analysed by high performance liquid chromatography (HPLC) using fluorescence detection. The results indicated that IVM produced a significantly higher maximum plasma concentration (C(max): 116.80+/-10.79 ng/ml) with slower absorption (t(max): 0.23+/-0.09 day) and larger area under the concentration versus time curve (AUC: 236.79+/-41.45 ng day/ml) as compared with DRM (C(max): 86.47+/-19.80 ng/ml, t(max): 0.12+/-0.05 day, AUC: 183.48+/-13.17 ng day/ml) following oral administration of both drugs; whereas no significant differences were observed on the pharmacokinetic parameters between IVM and DRM after subcutaneous administrations. In addition, subcutaneously given IVM and DRM presented a significantly lower maximum plasma concentration (C(max): 66.80+/-9.67 ng/ml and 54.78+/-11.99 ng/ml, respectively) with slower absorption (t(max): 1.40+/-1.00 day and 1.70+/-0.76 day, respectively) and larger area under the concentration versus time curve (AUC: 349.18+/-47.79 ng day/ml and 292.10+/-78.76 ng day/ml, respectively) as compared with the oral administration of IVM and DRM, respectively. No difference was observed for the terminal half-lives ((t(1/2lambda(z)) and mean residence times (MRT) of both molecules. Considering the pharmacokinetic parameters, IVM and DRM could be used by the oral or subcutaneous route for the control of parasitic infection in dogs.     

Pretreatment with the inducers rifampicin and phenobarbital alters ivermectin gastrointestinal disposition

Ballent, M., Lifschitz, A., Virkel, G., Mate, L., & Lanusse, C. Pretreatment with the inducers rifampicin and phenobarbital alters ivermectin gastrointestinal disposition. J. vet. Pharmacol. Therap. 33 , 252–259. The goal of the study was to evaluate the effects of rifampicin (RFP) and phenobarbital (PBT) on the plasma and gastrointestinal disposition kinetics of ivermectin (IVM) subcutaneously administered to Wistar rats. Fifty seven rats were used. Animals in Group I were the noninduced (control) group. Those in Groups II and III received a treatment with RFP (160 mg/day) and PBT (35 mg/day), respectively, both given orally during eight consecutive days as induction regimen. The IVM pharmacokinetic study was started 24 h after the RFP and PBT last administration. Animals received IVM (200 μg/kg) by subcutaneous injection. Rats were sacrificed between 6 h and 3 days after IVM administration. Blood and samples of liver tissue, intestinal wall and luminal content of jejunum were collected from each animal. IVM concentrations were measured by high performance liquid chromatography. IVM disposition kinetics in plasma and tissues was significantly modified by the PBT treatment, but not by RFP. Despite the enhanced CYP3A activity observed after the pretreatment with RPF and PBT, there were no marked changes on the percentages of IVM metabolites recovered from the bloodstream in induced and noninduced animals. An enhanced P‐glycoprotein‐mediated intestinal transport activity in pretreated animals (particularly in PBT pretreated rats) may explain the drastic changes observed on IVM disposition.     

Pharmacokinetics of doramectin and ivermectin after oral administration in horses

A study was undertaken in order to compare plasma disposition kinetic parameters of doramectin (DRM) and ivermectin (IVM) in horses after oral administration. Ten crossbreed adult horses, clinically healthy, weighing 380-470 kg body weight (bw) were selected for study. Faecal examinations were performed to determine faecal parasite egg counts. Horses were allocated to two groups of five animals to provide an even distribution considering the variables sex, body weight and faecal egg count. Group I, were treated with an oral paste formulation of IVM at 0.2 mg/kg b/w and Group II, were treated with an oral dose of 0.2 mg/kg bw of DRM prepared as paste from the injectable formulation for oral administration. Blood samples were collected by jugular puncture between 0 h and 75 days post-treatment. Plasma was separated and later solid phase extraction and derivatization samples were analysed by high performance liquid chromatography (HPLC); a computerised kinetic analysis was carried out. Data were compared using the Mann-Whitney U-test.The mean plasma concentrations of DRM and IVM after oral administration in horses were detected until 30 and 20 days, respectively. Both drugs showed similar patterns of absorption and no significant differences were found for peak concentration, the time to peak concentration, or for absorptive half-life. The terminal elimination half-life was significantly (P<0.05) longer in the DRM treated group than for the IVM treated group. The differences observed in the elimination half-life explain the longer mean residence time and high values of area under the concentration time curve for the group treated with DRM, which are 30% higher than those of the IVM group. Considering its pharmacokinetics, tolerance and anthelmintic efficacy, the oral administration of DRM, could be an alternative to IVM for the control of parasitic diseases of horses.     

Pharmacokinetics of ivermectin in zebu Gobra (Bos indicus)

Plasma disposition kinetics of ivermectin was evaluated in a West African cattle breed. Five clinically healthy zebu Gobra cattle (Bos indicus) weighing 220-270 kg were treated (0.2 mg kg-1) with a commercially available ivermectin formulation for cattle. Blood samples were collected by jugular puncture at different times between 0.5 h and 40 days post-treatment. After plasma extraction and derivatization, samples were analysed by HPLC with fluorescence detection. Ivermectin was detected in plasma between 30 min and 20 days post-treatment. The observed peak plasma concentration (Cmax) was 46.3+/-13.8 ng ml-1 and the time to reach Cmax (t(max)) was 0.9+/-0.2 day. The values for the absorption half-life (t1/2ab) and the elimination half-life (t1/2el) were 0.3+/-0.2 and 2.8+/-0.7 days, respectively. The calculated area under the concentration-time curve (AUC) was 185.2+/-12.1 ng day ml-1 and the mean residence time (MRT) was 4.2+/-1.3 days. The availability of ivermectin is low in zebu Gobra in comparison to other breeds cattle but equivalent to that reported in the yak and is likely to be due to physiological characteristics of this breed.     

Effect of parasitism on the pharmacokinetic disposition of ivermectin in lambs

The aim of this study was to investigate the effect of parasitism on plasma availability and pharmacokinetic behaviour of ivermectin (IVM) in lambs. Fourteen greyface Suffolk lambs (26.8 +/- 2.2 kg body weight) were selected for this study. Seven pairs of lambs were allocated into two groups in order to obtain an approximately even distribution. Group I (non-parasitized) was pre-treated by three repeated administrations of 5 mg/kg of fenbendazole (Panacur), in order to maintain a parasite-free condition. The lambs in group II (parasitized) did not receive any anthelmintic treatment and the natural infection was sustained by an oral inoculation of infective stages of nematode parasites. After the 85-day pre-treatment period both groups of animals were treated with IVM (200 microg/kg, Ivomec) by subcutaneous injection in the shoulder area. Both groups of animals were maintained under similar conditions of feeding and management. Blood samples were collected by jugular puncture at different times between 0.5 h and 25 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 unpaired Student's t-test. The parent molecule was detected in plasma between 30 min and either 12 (parasitized) or 20 (no parasitized) days post-IVM treatment. The area under the curve values of the parasitized group (75.2 +/- 15.5 ng x d/ml) were significantly lower that those observed in the parasite-free group (134.3 +/- 15.7 ng x d/ml). The mean residence time (MRT) of the parasitized group (2.93 +/- 0.16 days) was significantly lower than the MRT of healthy group (3.93 +/- 0.29 days). The results of this study have shown that a change in body condition followed by a parasitic infection is associated with significant changes in plasma disposition of IVM when it is administered subcutaneously to parasitized lambs. Therefore, variations in the condition induced by parasitism should be considered when these anthelmintics are used for treating parasitized animals.     

Breed-related plasma disposition of ivermectin following subcutaneous administration in Kilis and Damascus goats

Many factors related with drug and animals affect the plasma disposition of endectocides including ivermectin (IVM). The aim of the present study was to investigate the breed differences in pharmacokinetics of IVM in goats following subcutaneous administration. Two different goat breeds (Kilis and Damascus goats) were allocated into two treatment groups with respect to breed. The injectable formulation of IVM was administered subcutaneously at a dose rate of 0.2 mg/kg bodyweight. Blood samples were collected before treatment and at various times between 1 h and 40 days after treatment and the plasma samples were analysed by high performance liquid chromatography (HPLC) using fluorescence detection. The results indicated that the plasma disposition of IVM was substantially affected by breed differences following subcutaneous administration in goats. The last detectable plasma concentration (t_last) of IVM was significantly later in Kilis goats (38.33 days) compared with Damascus goats (22.50 days). Although, there were no significant differences on C_max (10.83 ng/ml vs. 10.15 ng/ml) and t_max (2.75 days vs. 2.33 days) values; the area under the concentration–time curve-AUC (110.26 ng.d/ml vs. 73.38 ng.d/ml) the terminal half-life-t_1/2λz (5.65 days vs. 3.81 days) and the mean plasma residence time-MRT (9.31 days vs. 6.35 days) were significantly different in Kilis goats compared with Damascus goats, respectively. The breed-related difference observed on the plasma disposition of IVM between Kilis and Damascus goats could be attributable to different excretion pattern or specific anatomical and/or physiological characteristics such as body fat composition of each breed.