Plasma Disposition, Faecal Excretion, Metabolism and Chirality of Anthelmintic Drugs in Horses

The plasma disposition and faecal excretion of oxfendazole (FBZ.SO), fenbendazole (FBZ) and oxibendazole (OBZ), and enantiospecific disposition of FBZ.SO were investigated in horses following oral administration at a dose rate of 10 mg/kg. Fenbendazole and FBZ.SO were metabolised extensively to the sulphone metabolite. Significantly greater plasma concentrations were found for sulphone (SO2) metabolites than for the parent molecules of FBZ and FBZ.SO. The sulphone metabolite is known to have relatively very low or no anthelmintic activity. Significantly higher mean maximum concentration (Cmax) and larger area under the concentration time curve (AUC) of parent molecules were obtained for FBZ.SO (Cmax: 0.35+/-0.07 mug/ml, AUC: 4.40+/-0.90 fig.h/ml) compared to FBZ (Cmax- 0.04+/-0.01mug/ml, AUC: 0.61+/-0.01 mug.h/ml). At the same oral dose rate, it is possible that FBZ.SO produces greater activity in the systemic circulation than FBZ since the plasma concentration of active metabolite of FBZ.SO was larger than that of FBZ however the tubulin binding of FBZ.SO is much lower than FBZ and activity probably reflects both concentration present and inherent affinity for the known receptor conforming activity. High concentrations of FBZ in the gut following FBZ administration could confer good activity on the parent compound for gastrointestinal parasites. The estimated plasma concentrations of OBZ from samples were very low (Cmax- 0.006 fig/ml). In faeces the highest faecal excretion was determined at 24 h for all molecules. A high FBZ concentration (~20% of parent molecule) was found in the faecal samples after FBZ.SO administration although faecal concentrations of administered moiety were always higher. Enantiospecific analysis of FBZ.SO showed that the first enantiomer (FBZ.SO-1) was predominant in six of the eight animals whereas in two animals the second enantiomer dominated in the plasma samples. The effect of piperonyl butoxide, a cytochrome P450 inhibitor was determined on the pharmacokinetic and chiral disposition of FBZ.SO in ponies. Oxfendazole was given intravenously at a dose rate of 10 mg/kg bodyweight and piperonyl butoxide was administered by nasogastric intubation at a dose rate of 31 mg/kg bodyweight, 30 minutes prior to FBZ.SO administration. The plasma concentrations of FBZ.SO and its sulphide and sulphone metabolites were determined following administration of FBZ.SO alone or with PB. It was shown that piperonyl butoxide significantly inhibited the metabolism of FBZ.SO and increased its plasma concentration. It was apparent that one of the FBZ.SO enantiomers (FBZ.SO-2) was metabolised much more rapidly than the other enantiomer (FBZ.SO-1). On the other hand, the plasma concentrations of FBZ.SO-2 were higher than those of FBZ.SO-1 when the animals were given FBZ.SO with piperonyl butoxide. Thus the metabolism or excretion of FBZ.SO-2 was inhibited by piperonyl butoxide more effectively than that of FBZ.SO-1. Hepatic microsome samples were prepared from horse liver tissue to determine the in vitro metabolism of FBZ.SO, FBZ and OBZ with and without piperonyl butoxide. Only the sulphone metabolite was formed after FBZ.SO incubation and the sulphone, sulphoxide and hydroxy metabolite were formed after FBZ incubation. The sulphonation pathway of the metabolism of FBZ.SO and FBZ was inhibited significantly by piperonyl butoxide. The extent of metabolism for FBZ.SO and FBZ was significantly higher when the anthelmintics were incubated alone than in the presence of piperonyl butoxide. The enantiospecific metabolism was also determined following incubation of FBZ.SO as a racemate substrate and following incubation of FBZ as a prochiral drug with and without piperonyl butoxide. Microsomal metabolism was apparently enantiospecific since the enantiomers were metabolised differently from each other. There was a marked change in the enantiomer ratio when FBZ.SO was incubated with piperonyl butoxide. Fenbendazole (FBZ) metabolism to sulphoxide (FBZ.SO) was also shown to be enantiospecific since FBZ.SO-1 predominated in the reaction mixture. Piperonyl butoxide affected the enantiospecific character of the metabolism. Oxibendazole (OBZ) was metabolised extensively to its unidentified metabolites (Ml, M2, M3 and M4) and piperonyl butoxide significantly inhibited the metabolism of OBZ. Three unidentified metabolites (Ml, M2 and M4) were significantly decreased and one unidentified metabolite (M3) was significantly increased when OBZ was incubated with piperonyl butoxide. The pharmacokinctic disposition and faecal excretion of IVM, MXD and DRM were reported in horses following oral administration at a dose rate of 0.2 mg/kg. Large interindividual variations of kinetic parameters were observed from animals in this study. A similar pattern of absorption and time till Cmax (tmax) were found

Comparative pharmacokinetics of levamisole-oxyclozanide combination in sheep and goats following per os administration

Since there is no registered anthelmintic drug available for use in goats, extra-label use of drugs is a common practice in most countries. The aim of the present study was to compare the pharmacokinetic disposition of levamisole (LVM)-oxyclozanide (OXZ) combination in sheep and goats following per os administration. Goats (n = 8) and sheep (n = 8) 12- to 16-months-old were used for this study. The animals received tablet formulation of LVM and OXZ combination orally at a dose of 7.5 mg/kg and 15 mg/kg body weight, respectively. Blood samples were collected by jugular vein at different times between 5 min and 120 h after drug administrations. The plasma concentrations of LVM and OXZ were analyzed by HPLC following liquid-liquid phase extraction procedures. The plasma concentrations and systemic availabilities of both LVM and OXZ in goats were lower and the plasma persistence of LVM was shorter compared with those observed in sheep. Terminal half-lives (t1/2z) of both molecules are shorter in goats compared with those in sheep. Goats treated with LVM-OXZ combination at the recommended dose for sheep may result in a reduced efficacy, because of under-dosing, which may increase the risk of drug resistance in parasites. Increased or repeated dose could be a strategy to provide higher plasma concentration and thus to improve the efficacy against the target parasites in goats compared with sheep. However, some adverse reactions may occur since LVM has relatively very narrow therapeutic index due to its nicotine-like structure and effect

Pharmacokinetic features of the antiparasitic macrocyclic lactones

The macrocyclic lactones have pharmacokinetic properties which enhance their use against endo- and ectoparasites in animals and man. The most consistent physico-chemical feature of the group which contributes to their kinetic characteristics is high lipid solubility. This appears to be necessary for their pharmacodynamic action as well as common kinetic features such as large volumes of distribution and the influence of body fat composition on their disposition. They are used in all domestic animal species and are undoubtedly influenced by the anatomical and physiological differences in these species, however body fat composition also appears to exert a major influence on distribution, metabolism and persistence between species and between breeds and individuals. A myriad of formulations have been developed to enhance the convenience of administration in the different domestic animals and the macrocyclic lactones are delivered orally, subcutaneously and topically to good effect. Lipid based excipients have been developed in "depot" formulations to extend the period of effective prevention of parasite re-infection. Subtle structural changes have been made to the macrocyclic lactone molecules to reduce distribution to the central nervous system and mammary gland, thus allowing use of some compounds such as selamectin (SLM) in "toxicity sensitive" breeds of collie dog which lack P-glycoprotein efflux systems in their central nervous systems and the use of eprinomectin (EPM) in dairy cattle with a nil-milk withdrawal period. Gender differences exist in the pharmacokinetics of these compounds which may be associated with body (fat) composition or metabolism. Feeding may also reduce the availability of macrocyclic lactones which bind particulate digestive material and parasitism may impact the kinetics of the drugs because parasitized animals have altered pathophysiological processes, especially in the gastro intestinal tract but also because of the impact which parasitism may have on the body condition (and fat deposition) in animals. The pharmacokinetics of macrocyclic lactones may be affected by co-administration with compounds which interfere with P-glycoprotein transporters and these interactions have been explored as possible mechanisms for enhancing the effectiveness of these antiparasitics. The objective of this article is to provide a comprehensive review of the pharmacokinetics of macrocyclic lactones and to interpret where that information may prove clinically useful.Peer reviewe

An Updated Review of Tetrodotoxin and Its Peculiarities

Tetrodotoxin (TTX) is a crystalline, weakly basic, colorless organic substance and is one of the most potent marine toxins known. Although TTX was first isolated from pufferfish, it has been found in numerous other marine organisms and a few terrestrial species. Moreover, tetrodotoxication is still an important health problem today, as TTX has no known antidote. TTX poisonings were most commonly reported from Japan, Thailand, and China, but today the risk of TTX poisoning is spreading around the world. Recent studies have shown that TTX-containing fish are being found in other regions of the Pacific and in the Indian Ocean, as well as the Mediterranean Sea. This review aims to summarize pertinent information available to date on the structure, origin, distribution, mechanism of action of TTX and analytical methods used for the detection of TTX, as well as on TTX-containing organisms, symptoms of TTX poisoning, and incidence worldwide.info:eu-repo/semantics/publishedVersio

Influence of the Route of Administration on Therapeutic Efficacy of Ivermectin in Saanen and Damascus Goats Naturally Infected with Trichostrongylidae spp.

The aims of this study were to compare the therapeutic efficacy of ivermectin after subcutaneous, per os and pour-on administration in Saanen goats naturally infected with Trichostrongylidea spp. and to evaluate the efficacy of ivermectin pour-on in Damascus goats with similar gastrointestinal nematodes. After body weighing and faecal sample collection on day 0 (pre-treatment day), 45 Saanen goats were weighed, faecal sampled and allocated on the basis of day -3 faecal egg counts (FEC) to four treatment groups (n=9 in each group). Saanen goats were then treated with a single dose of ivermectin at a dose rate of 0.2 mg/kg by subcutaneous injection or oral administration and 0.5 mg/kg or 1 mg/kg by topical application. Nine Saanen goats were kept as non-medicated control. Fifteen Damascus goats were divided two groups. The first group (n=9) received ivermectin pour-on as a single dose of 0.5 mg/kg and the second group (n= 6) served as a non-medicated control. The efficacy was measured on the basis of the reduction of the egg output and the evaluation of the results from larval differentiation on 14 days post-treatment. In Saneen goats, ivermectin provided equally excellent (100%) therapeutic efficacy after subcutaneous or oral administration whereas ivermectin pour-on treatment at a dose of 0.5 mg/kg and 1.0 mg/kg reduced pretreatment FEC by 96.5% and 99.9%, respectively. No statistically significant difference was found between 1.0 mg/kg of ivermectin by topical application and the ivermectin subcutaneous and oral treated groups for post treatment FEC whereas the efficacy of ivermectin pour-on at 0.5 mg/kg was significantly lower than that for each of the other 3 treatment groups. In Damascus goat, the therapeutic efficacy of 0.5 mg/kg ivermectin pour-on was recorded as only 30.7%

Comparative pharmacokinetics and bioavailability of albendazole sulfoxide in sheep and goats, and dose-dependent plasma disposition in goats

Background: The aims of this study were to compare the pharmacokinetics of albendazole sulfoxide (ABZ-SO, ricobendazole) in goats and sheep at a dose of 5 mg/kg bodyweight (BW), after intravenous (IV) and subcutaneous (SC) administrations, and to investigate the effects of increased doses (10 and 15 mg/kg BW) on the plasma disposition of ABZ-SO in goats following SC administration. A total of 16 goats (Capra aegagrus hircus, eight males and eight females) and 8 sheep (Ovis aries, four males and four females) 12-16 months old and weighing 20-32 kg, were used. The study was designed according to two-phase crossover study protocol. In Phase-1, eight sheep were assigned as Group I and 16 goats were allocated into two groups (Group II and Group III). ABZ-SO was applied to Group I (sheep) and Group II (goats) animals subcutaneously, and to Group III (goats) animals intravenously, all at a dose rate of 5 mg/kg BW. In Phase-2, the sheep in the Group I received ABZ-SO intravenously in a dose of 5 mg/kg BW; the goats in Group II and Group III received ABZ-SO subcutaneously at a dose of 10 mg/kg and 15 mg/kg BW, respectively. Blood samples were collected from the jugular vein at different times between 1 and 120 h after drug administrations. The plasma concentrations of ABZ-SO and its metabolites were analysed by high performance liquid chromatography. Results: In goats, the area under the curve, terminal half-life and plasma persistence of ABZ-SO were significantly smaller and shorter, respectively, compared with those observed in sheep following both IV and SC administrations at a dose of 5 mg/kg BW. On the other side, dose-dependent plasma dispositions of ABZ-SO were observed following SC administration at increased doses (10 and 15 mg/kg) in goats. Conclusions: Consequently, ABZ-SO might be used at higher doses to provide higher plasma concentration and thus to achieve greater efficacy against the target parasites

The impact of nano/micro-plastics toxicity on seafood quality and human health: facts and gaps

International audienceContamination of the food and especially marine environment with nano/micro-plastic particles has raised serious concern in recent years. Environmental pollution and the resulting seafood contamination with microplastic (MP) pose a potential threat to consumers. The absorption rate of the MP by fish is generally considered low, although the bioavailability depends on the physical and chemical properties of the consumed MP. The available safety studies are inconclusive, although there is an indication that prolonged exposure to high levels of orally administered MP can be hazardous for consumers. This review details novel findings about the occurrence of MP, along with its physical and chemical properties, in the marine environment and seafood. The effect of processing on the content of MP in the final product is also reviewed. Additionally, recent findings regarding the impact of exposure of MP on human health are discussed. Finally, gaps in current knowledge are underlined, and the possibilities for future research are indicated in the review. There is an urgent need for further research on the absorption and bioavailability of consumed MP and in vivo studies on chronic exposure. Policymakers should also consider the implementation of novel legislation related to MP presence in food