Biomedical subjects

G Virkel

Publications and source records attributed to G Virkel.

At least 19 recordsLinked to original sources

PubMed2006

Assessment of the main metabolism pathways for the flukicidal compound triclabendazole in sheep.

Triclabendazole (TCBZ) is an halogenated benzimidazole (BZD) compound worldwide used to control immature and adult stages of the liver fluke Fasciola hepatica. The purpose of this investigation was to characterize in vitro the patterns of hepatic and ruminal biotransformation of TCBZ and its metabolites in sheep. TCBZ parent drug was metabolized into its sulphoxide (TCBZSO), sulphone (TCBZSO2) and hydroxy derivatives by sheep liver microsomes. The same microsomal fraction was also able to oxidize TCBZSO into TCBZSO2 and hydroxy-TCBZSO (HO-TCBZSO). TCBZ sulphoxidation was significantly (P < 0.001) inhibited after inactivation of the flavin-monooxygenase (FMO) system (77% inhibition) as well as in the presence of the FMO substrate methimazole (MTZ) (71% inhibition). TCBZ sulphoxidative metabolism was also reduced (24% inhibition, P < 0.05) by the cytochrome P450 inhibitor piperonyl butoxide (PB). The rate of TCBZSO conversion into TCBZSO2 was also significantly inhibited by PB (55% inhibition), MTZ (52% inhibition) and also following FMO inactivation (58% inhibition). The data reported here indicate that the FMO is the main enzymatic pathway involved in TCBZ sulphoxidation (ratio FMO/P450 = 3.83 +/- 1.63), although both enzymatic systems participate in a similar proportion in the sulphonation of TCBZSO to form the sulphone metabolite (ratio FMO/P450 = 1.31 +/- 0.23). Additionally, ketoconazole (KTZ) did not affect TCBZ sulphoxidation but decreased (66% inhibition, P < 0.05) the formation of TCBZSO2. Similarly, inhibition of TCBZSO2 production was observed after incubation of TCBZSO in the presence of KTZ and erythromycin (ETM). Conversely, thiabendazole (TBZ) and fenbendazole (FBZ) did not affect the oxidative metabolism of both incubated substrates. The sheep ruminal microflora was able to reduce the sulphoxide (TCBZSO) into the parent thioether (TCBZ). The ruminal sulphoreduction of the HO-TCBZSO derivative into HO-TCBZ was also demonstrated. The rate of sulphoreduction of HO-TCBZSO was significantly (P < 0.05) higher than that observed for TCBZSO. The metabolic approach tested here contributes to the identification of the different pathways involved in drug biotransformation in ruminant species. These findings on the pattern of hepatic and ruminal biotransformation of TCBZ and its main metabolites are a further contribution to the understanding of the pharmacological properties of widely used anthelmintics in ruminants. Comprehension of TCBZ metabolism is critical to optimize its flukicidal activity.

Animals↗

PubMed2006

Sex-related differences in the gastrointestinal disposition of ivermectin in the rat: P-glycoprotein involvement and itraconazole modulation.

Ivermectin (IVM), a macrocyclic lactone used as antiparasite agent, has been reported as a P-glycoprotein (P-gp) substrate. The participation of P-gp in the IVM excretion process has been previously demonstrated. Sex-related differences in the kinetic behaviour of some macrocyclic lactone compounds have been observed. The aim of this work was to characterize in-vivo the comparative gastrointestinal disposition of IVM in male and female rats. The sex-related influence on the itraconazole (ITZ) modulation of P-gp-mediated IVM intestinal transport was also assessed. Sixty Wistar rats (30 male, 30 female) received IVM alone or co-administered with ITZ. Rats were killed between 6 and 72 h after treatment and blood, gastrointestinal tissues and lumen contents were collected. IVM concentrations were determined by high performance liquid chromatography. Substantial sex-related differences in the IVM disposition kinetics were observed. Higher IVM systemic availability was observed in female rats. The ITZ-mediated modulation of the IVM disposition kinetics had a differential impact between male and female rats. Co-administration with ITZ resulted in a marked increase in the IVM concentrations in the wall tissue from different portions of the gastrointestinal tract of male rats. The presence of ITZ induced drastic sex-related changes on the P-gp-mediated IVM gastrointestinal disposition.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

Modulation of the P-glycoprotein-mediated intestinal secretion of ivermectin: in vitro and in vivo assessments.

The everted gut sac method was used to assess the role of the P-glycoprotein (P-gp) on the intestinal secretion of ivermectin (IVM), an antiparasitic widely used in human and veterinary medicine. The work included the evaluation of two different P-gp modulators [itraconazole (ITZ) and valspodar (PSC833)] used at equimolar doses in the rat. Furthermore, the influence of both P-gp modulator agents on the disposition kinetics of IVM in plasma, liver, and gastrointestinal tissues was characterized. For the in vitro experiments, ileal sacs were incubated with IVM (3 microM) in the presence or absence of either ITZ (10 microM) or PSC833 (10 microM). In the in vivo experiments, male Wistar rats were randomly allocated to three groups (n=18) and subcutaneously treated with IVM (200 microg/kg-1), alone and coadministered with ITZ (5 mg, two doses) or PSC833 (8.6 mg, two doses). Animals were sacrificed between 6 and 96 h. Blood, liver, and gastrointestinal samples were collected. IVM concentrations were determined by high performance liquid chromatography. The rate of IVM accumulation in the intestinal wall of everted sacs was significantly higher after its incubation with ITZ (0.115 nmol/g/min) and PSC833 (0.238 nmol/g/min) than that obtained after the incubation without the P-gp modulators (0.016 nmol/g/min). In agreement with the in vitro experiment, the presence of ITZ and PSC833 induced an enhancement in the concentrations of IVM in plasma and gastrointestinal tissues. The results obtained in the current work, both under in vivo and in vitro conditions, confirm the relevance of P-gp-mediated transport to the intestinal secretion of IVM.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

Doramectin concentration profiles in the gastrointestinal tract of topically-treated calves: Influence of animal licking restriction.

Endectocide compounds are extensively used for broad-spectrum parasite control and their topical administration to cattle is widespread in clinical practice. Pour-on formulations of moxidectin, ivermectin, eprinomectin and doramectin (DRM) are marketed internationally for use in cattle. However, variability in antiparasitic efficacy and pharmacokinetic profiles has been observed. Although the tissue distribution pattern for different endectocide molecules given subcutaneously to cattle has been described, only limited information on drug concentration profiles in tissues of parasite location after topical treatment is available. Understanding the plasma and target tissue kinetics for topically-administered endectocide compounds is relevant to optimise their therapeutic potential. The current work was designed to measure the plasma and gastrointestinal (GI) concentration profiles of DRM following its pour-on administration to calves. The influence of natural licking behaviour of cattle on DRM concentration in mucosal tissue and luminal content of different GI sections was evaluated. The trial was conducted in two experimental phases. In Phase I, the DRM plasma kinetics was comparatively characterised in free-licking and in 2-day licking-restricted (non-licking) calves. The pattern of distribution of topical DRM to mucosal and luminal contents from abomasum, duodenum, ileum, caecum and spiral colon was assessed in free-licking and non-licking calves restricted over 10 days post-administration (Phase II). The prevention of licking caused marked changes on the plasma and GI kinetics of DRM administered pour-on. In 2-day licking restricted calves, DRM systemic availability was significantly lower (29%) than in free licking animals during the first 9 days post-treatment. Following a 10-day long licking restriction period, DRM concentrations profiles in both mucosal tissue and luminal contents of the GI tract were markedly higher in animals allowed to lick freely. This enhancement in drug concentrations in free-licking compared to non-licking calves, was particularly pronounced in the abomasal (38-fold higher) and duodenal (six-fold higher) luminal content. As shown earlier for ivermectin, licking behaviour may facilitate the oral ingestion of topically-administered DRM in cattle. This would be consistent with the marked lower drug concentration profiles measured in the bloodstream and GI tract of the animals prevented from licking. The work reported here provides relevant information on the pattern of DRM distribution to the GI tract after pour-on treatment, and contributes to understand the variability observed in the antiparasitic persistence of topically-administered endectocides in cattle. The implications of natural licking in topical treatments are required to be seriously assessed to achieve optimal parasite control and to design parasitological and pharmacological studies within the drug approval process.

Administration, Topical↗

PubMed2005

Moxidectin and ivermectin metabolic stability in sheep ruminal and abomasal contents.

The oral administration of macrocyclic lactones to sheep leads to poorer efficacy and shorter persistence of the antiparasitic activity compared to the subcutaneous treatment. Gastrointestinal biotransformation occurring after oral treatment to ruminant species has been considered as a possible cause of the differences observed between routes of administration. The current work was addressed to evaluate on a comparative basis the in vitro metabolism of moxidectin (MXD) and ivermectin (IVM) in sheep ruminal and abomasal contents. Both compounds were incubated under anaerobic conditions during 2, 6 and 24 h in ruminal and abomasal contents collected from untreated adult sheep. Drug concentrations were measured by high-performance liquid chromatography with fluorescence detection after sample clean up and solid phase extraction. Neither MXD nor IVM suffered metabolic conversion and/or chemical degradation after 24-h incubation in ruminal and abomasal contents collected from adult sheep. Unchanged MXD and IVM parent compounds represented between 95.5 and 100% of the total drug recovered in the ruminal and abomasal incubation mixtures compared with those measured in inactive control incubations. The partition of both molecules between the solid and fluid phases of both sheep digestive contents was assessed. MXD and IVM were extensively bound (>90%) to the solid material of both ruminal and abomasal contents collected from sheep fed on lucerne hay. The results reported here confirm the extensive degree of association to the solid digestive material and demonstrates a high chemical stability without evident metabolism and/or degradation for both MXD and IVM in ruminal and abomasal contents.

Abomasum↗

PubMed2004

Effect of the ionophore antibiotic monensin on the ruminal biotransformation of benzimidazole anthelmintics.

The benzimidazole (BZD) anthelmintics, netobimin (NTB) pro-drug and albendazole sulphoxide (ABZSO) are reduced to albendazole (ABZ) by ruminal microflora. The aim of the current work was to evaluate the influence of the ionophore monensin (MON) on the in vitro biotransformation of NTB and ABZSO by sheep ruminal fluid. Ruminal fluid, collected from Corriedale sheep, was preincubated (24 h) either without (control) or with known MON concentrations (0.5, 1.5 and 3.0 microg/mL) at 38 degrees C under a CO2 atmosphere. Afterwards, aliquots from both MON-pretreated and control ruminal fluid samples were incubated (30 and 60 min) with 2 microg/mL of either NTB or ABZSO. Incubated samples were chemically extracted and analysed by High Performance Liquid Chromatography to quantify the metabolites formed. The rate of ABZ production after 30 min of NTB incubation with control ruminal fluid was 0.023 microg/min. Conversely, the rates of ABZ formation were significantly (P<0.05) lower (0.009, 0.011 and 0.013 microg/min) when NTB was incubated with ruminal fluid pretreated with MON (at 0.5, 1.5 and 3.0 microg/mL, respectively). After both incubation periods, the reduction of ABZSO to ABZ was 22 to 70% lower when the ruminal fluid was preincubated with the different MON concentrations. The lower ABZ production observed in the presence of MON may result in a modified availability of this molecule in the gastrointestinal (GI) tract and hence, on its anthelmintic efficacy against GI nematodes.

Albendazole↗

PubMed2004

Integrated pharmacological assessment of flubendazole potential for use in sheep: disposition kinetics, liver metabolism and parasite diffusion ability.

Flubendazole (FLBZ) is a broad spectrum benzimidazole methylcarbamate anthelmintic widely used in poultry and swine. However, there is no information available on the pharmacological behaviour of FLBZ in ruminants. The work reported here was addressed to evaluate the potential of FLBZ for use in sheep. The integrated assessment included evaluation of FLBZ and metabolites plasma disposition kinetics, liver metabolism and ex vivo ability to diffuse into the cestode parasite Moniezia benedeni. In a cross-over kinetic study, six healthy Corriedale sheep were treated with FLBZ by intravenous (i.v.) (4% solution) and intraruminal (i.r.) (4% suspension) administrations at the same dosage (5 mg/kg) with a 21-day washout period between treatments. Blood samples were collected between 0 and 72 h post-treatments. Sheep liver microsomes were incubated with 40 microm FLBZ and specimens of the cestode parasite M. benedeni, collected from untreated animals, were incubated (5-120 min) with FLBZ and its reduced (R-FLBZ) metabolite (5 microm). Samples of plasma, microsomal incubations and parasite material were prepared and analyzed by high-performance liquid chromatography to measure FLBZ and its metabolites. FLBZ parent drug showed a fast disposition being detected in the bloodstream up to 36 h after its i.v. administration. Both R-FLBZ and hydrolyzed FLBZ (H-FLBZ) metabolites were recovered in plasma as early as 5 min after the i.v. treatment in sheep. The plasma AUC ratios for R-FLBZ and FLBZ (AUC(R-FLBZ)/AUC(FLBZ)) were 4.07 i.v. and 5.55 i.r., respectively. R-FLBZ achieved a significantly higher (P < 0.01) C(max) value (0.14 microg/mL at 17.3 h post-treatment) than that observed for the parent drug FLBZ (0.04 microg/mL at 14.4 h post-treatment). Low plasma concentrations of FLBZ parent drug were measured between 6 and 48 h, and only trace concentrations of H-FLBZ were detected during a short period of time after the i.r. treatment. Consistently, sheep liver microsomes metabolized FLBZ into its reduced metabolite at a rate of 9.46 +/- 2.72 nmol/mg/h. Both FLBZ and R-FLBZ demonstrated a similar ability to quickly diffuse through the tegument of the cestode parasite. The data on FLBZ pharmacological behaviour presented here contribute to evaluate its potential to be developed as an anthelmintic for broad spectrum parasite control in ruminants.

Animals↗

PubMed2004

Comparative hepatic and extrahepatic enantioselective sulfoxidation of albendazole and fenbendazole in sheep and cattle.

The enantioselective sulfoxidation of the prochiral anthelmintic compounds albendazole (ABZ) and fenbendazole (FBZ) was investigated in liver, lung and small intestinal microsomes obtained from healthy sheep and cattle. The microsomal fractions were incubated with a 40 microM concentration of either ABZ or FBZ. Inhibition of the flavin-containing monooxygenase (FMO) system was carried out by preincubation with 100 microM methimazole (MTZ) either with or without heat pretreatment (2 min at 50 degrees C). ABZ and FBZ were metabolized to the (+) and (-) enantiomers of their sulfoxide metabolites, named albendazole sulfoxide (ABZSO) and oxfendazole (OFZ), respectively. ABZ sulfoxidation rates were higher (p < 0.001) than those observed for FBZ. The FMO-mediated liver sulfoxidation of ABZ was enantioselective (100%) toward the (+) ABZSO production in both species. Liver sulfoxidation of FBZ by FMO was also enantioselective toward (+) OFZ (sheep = 65%; cattle = 79%). Cytochrome P450 was found to be mainly involved in the production of (-) ABZSO in the liver. MTZ did not affect the sulfoxidation of ABZ by lung microsomes, which may indicate that FMO is not involved in the production of ABZSO in this tissue. A significant (p < 0.05) inhibition of (-) ABZSO production by liver microsomes was observed after ABZ incubation in the presence of erythromycin (cattle = 21%) and ketoconazole (sheep = 36%). Both CYP3A substrates induced a reduction in the production of (-) ABZSO (sheep = 67-78%, cattle = 50-78%) by lung microsomes. Overall, the results reported here contribute to the identification of the metabolic pathways involved in the biotransformation of benzimidazole anthelmintics extensively used for parasite control in ruminants.

Albendazole↗

PubMed2003

A detailed assessment of the pattern of moxidectin tissue distribution after pour-on treatment in calves.

The use of topical (pour-on) administration of endectocide drugs in cattle has reached world-wide acceptance. However, only limited information is available on the kinetic behaviour for topically administered moxidectin (MXD). To improve our understanding of the relationship between pharmacokinetics and efficacy for pour-on preparations, MXD concentration profiles were measured in tissues of endo- and ectoparasites location over 35 days postadministration. MXD distribution to the fluid content and mucosal tissue of the abomasum and different intestinal sections (duodenum, ileum, caecum and colon) was assessed. The comparative patterns of MXD distribution to skin and hypodermic tissue from different anatomical sites (backline, rib cage, thigh and face) were also investigated following the pour-on administration. Wide tissue distribution and long residence time characterized the kinetics of topically administered MXD. MXD was recovered between 1 and 35 days post-treatment in all the tissues investigated. The highest MXD availabilities were observed in the skin layers at the site of administration (backline) and in the fat tissue. The fluid contents of different intestinal sections showed MXD concentrations higher than those measured in their respective mucosal tissues, particularly at day 1 post-treatment. MXD concentrations in the skin (epidermis + dermis) were higher than those measured in the hypodermic tissue. Large differences in the availability of MXD in skin from different anatomical regions (backline > rib cage > thigh > face) were observed. The low plasma and the high skin availability indicate the formation of a skin depot of the drug, being released slowly to the plasma and reaching concentrations in systemic tissues (abomasal mucosa, lungs, etc.) similar to those measured after subcutaneous administration. These findings demonstrate that target parasites may be exposed to markedly different drug concentrations according to their location sites, which is particularly relevant for ectoparasites located in different anatomical regions. Knowledge of the tissue distribution of topically administered endectocides contributes to understand the differences observed in efficacy and/or persistence of activity and to optimize their use in cattle.

Abomasum↗

PubMed2002

In vitro ruminal biotransformation of benzimidazole sulphoxide anthelmintics: enantioselective sulphoreduction in sheep and cattle.

The comparative in vitro sulphoreduction of the (+) and (-) enantiomers of albendazole sulphoxide (ABZSO) and oxfendazole (OFZ) by ruminal fluid obtained from sheep and cattle, was investigated, under anaerobic conditions, in this study. Ruminal fluid samples were obtained from Holstein steers fitted with a permanent rumen fistula and from Corriedale lambs via an oesophageal tube. Albendazole sulphoxide, incubated as either the racemic (rac) mixture or as each individual enantiomeric form, was extensively sulphoreduced to form albendazole (ABZ) by ruminal fluid from both species. The concentrations of ABZ formed at different incubation times were between 55 and 158% greater after the incubation of cattle ruminal fluid with (+) ABZSO, compared with that produced when (-) ABZSO was the incubated substrate. Similarly, the concentrations of ABZ were 1.3--3.0-fold higher when (+) ABZSO was incubated with sheep ruminal fluid. Significantly higher rates of depletion were observed for the (+) enantiomeric form when ABZSO was incubated with ruminal fluid from both species. The rates of ABZ formation from both ABZSO enantiomeric forms were significantly higher in sheep compared with cattle ruminal fluid. Fenbendazole (FBZ) was the metabolite formed after the incubation of the racemic form of OFZ with ruminal fluid obtained from both species. The metabolic profile of both OFZ enantiomers followed a similar pattern to that observed for ABZSO enantiomers. A bi-directional chiral inversion of one enantiomer into its antipode was observed. The (+) enantiomer appeared in the incubation medium when (-) ABZSO was the incubated substrate, and also the (-) antipode was detected after (+) ABZSO incubation with ruminal fluid obtained from both species. The results reported here demonstrate an enantioselective ruminal sulphoreduction of ABZSO and OFZ (substrate enantioselectivity). These findings contribute to interpret the chiral behaviour of benzimidazole-sulphoxide anthelmintics.

Administration, Oral↗

PubMed2002

Loperamide-induced enhancement of moxidectin availability in cattle.

Moxidectin (MXD) is a milbemycin endectocide compound active at extremely low dosages against a wide variety of nematode and arthropod parasites. Different pharmacological approaches are currently being tested to delay the bile-faecal elimination and to obtain increased systemic availability for endectocide molecules in ruminants. Loperamide (LPM) is an opioid derivative, whose main pharmacological action is to abolish intestinal propulsive peristaltic waves. The influence of LPM on the pattern of faecal excretion of MXD and on its plasma disposition following intravenous (i.v.) and subcutaneous (s.c.) administrations to cattle was evaluated in the current work. Parasite-free calves were treated with MXD given either alone at 200 microg/kg by i.v. (Experiment 1) and s.c. (Experiment 2) administrations or coadministered with LPM subcutaneously injected at 0.4 mg/kg. Blood and faecal samples were collected over a period of 20 (Experiment 1) and 40 (Experiment 2) days post-treatment. The recovered plasma and faecal samples were extracted and analysed by high-performance liquid chromatography (HPLC) using fluorescence detection. Significantly higher MXD plasma concentrations were obtained after the coadministration of MXD + LPM compared with treatments with MXD alone by both routes. The higher MXD plasma concentration profiles measured after the coadministration with LPM accounted for the significantly higher AUC values obtained following the i.v. (> 46%) and s.c. (> 38%) treatments. A reduced MXD body clearance was observed in the presence of LPM. The appearance of MXD in faeces was significantly delayed after the i.v. and s.c. coadministrations of MXD with LPM (T(1/2app)=5.87 and 10.6 h, respectively) than that observed after the treatment with MXD alone (T(1/2app)=3.48 and 5.12 h). A delayed MXD peak concentration in faeces collected from MXD + LPM-treated animals compared with those receiving MXD alone, was observed. The delayed intestinal transit time caused by LPM and a potential competition between MXD and LPM for the P-glycoprotein-mediated bile/intestinal secretion processes, may account for the enhanced MXD systemic availability measured in cattle in the current work.

Animals↗

PubMed2002

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.

Administration, Topical↗

PubMed2001

Albendazole sulphoxide enantiomeric ratios in plasma and target tissues after intravenous administration of ricobendazole to cattle.

The comparative concentration profiles of the (+) and (-) albendazole sulphoxide (ABZSO) enantiomers obtained in plasma and in selected target tissues/fluids after intravenous (i.v.) administration of a racemic formulation of ricobendazole (RBZ) to cattle were characterised. Fourteen Holstein calves received RBZ (racemic solution, 150 mg/mL) by i.v. administration at 7.5 mg/kg. Jugular blood samples were collected over 48 h post-treatment (plasma kinetic trial) and two animals were sacrificed at either 4, 12, 20, 28 or 32 h post-treatment to obtain samples of abomasal/small intestine mucosal tissue, abomasal/small intestine fluids, bile, liver and lung tissue (tissue distribution study). The (-)ABZSO enantiomer was depleted significantly faster from plasma compared with the (+)ABZSO antipode. The plasma AUC for (+)ABZSO (38.3 microg. h/mL) was significantly higher (P < 0.05) compared with that obtained for (-)ABZSO (20.5 microg. h/mL). The (+)ABZSO enantiomer was the predominant antipode measured in bile, abomasal fluid and abomasal mucosa. For instance, at 12 h post-treatment the (+)/(-) concentration ratios were: 12.9 (plasma), 1.62 (abomasal mucosa), 13.0 (abomasal fluid), 2.92 (intestinal mucosa), 9.87 (intestinal fluid) and 21.5 (bile). No marked differences between the concentration profiles of both enantiomers were observed in the liver tissue. Albendazole (ABZ) was recovered from the liver, lung and gastrointestinal (GI) mucosal tissues of RBZ-treated calves up to 32 h post-treatment, probably produced by a GI microflora-mediated sulphoreduction of RBZ. An enantioselective kinetic behaviour may account both for the faster depletion of the (-) enantiomer and for the higher availabilities of the (+) antipode observed in plasma and in most of the tissues/fluids investigated. The simultaneous evaluation of the plasma kinetics and tissue concentration profiles of both enantiomeric forms reported here, may help to interpret the relationship between chiral behaviour and pharmacological action for sulphoxide derivatives of benzimidazole (BZD) methylcarbamate anthelmintics.

Albendazole↗

PubMed2000

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.

Abomasum↗

PubMed2000

Comparative disposition of ricobendazole enantiomers after intravenous and subcutaneous administration of a racemic formulation to calves.

The enantioselective disposition kinetics of the benzimidazole anthelmintic, ricobendazole (RBZ), have been characterized after its intravenous (iv) and subcutaneous (sc) administration as a racemic formulation to cattle. The (+) and (-) RBZ enantiomeric forms were recovered in plasma after iv and sc administration of the racemic RBZ formulation, using a chiral phase based HPLC method. A biexponential plasma concentration versus time curve was observed for both RBZ enantiomers following the iv treatment. Total body clearance was higher for (-) RBZ (150.4 mL/h. kg) compared with that obtained for the (+) RBZ antipode (78.1 mL/h. kg). The elimination half-life of the (-) RBZ enantiomer was shorter (T1/2beta: 2.67 h) compared with the (+) enantiomer (T1/2beta: 5.41 h). The plasma availability (expressed as AUC) was significantly higher for (+) RBZ compared with that obtained for the (-) antipode following both treatments. The enantiomeric ratio in plasma at T(0) was close to unity (50% of each enantiomer); the analysis of the concentration ratios (+) RBZ/(-) RBZ, demonstrated an increase in the proportion of (+) RBZ during the time course of the kinetics after both iv and sc treatments. The results presented herein show the enantioselective disposition kinetics of RBZ in cattle and are a further contribution to the understanding of the kinetic behaviour of these sulphoxide-containing benzimidazole anthelmintics in ruminants.

Albendazole↗

PubMed2000

Depletion of moxidectin tissue residues in sheep.

The pattern of tissue depletion of moxidectin (MXD) subcutaneously administered to sheep was characterized in this study. MXD concentration profiles were determined in muscle, fat, and liver and at the site of injection following administration of a formulation combining MXD (0.5% w/v) with a standard 6 in 1 clostridial vaccine. Thirty-five (35) parasite-free Lincoln sheep were treated with the MXD injectable formulation at a dose rate of 0.2 mg of MXD/kg of live weight, administered subcutaneously on the inner surface of the thigh. Treated animals were sacrificed in randomly selected groups of six sheep weekly from day 21 until day 49 post-treatment. Three nontreated animals were sacrificed to obtain blank tissue samples to validate the analytical methodology. MXD concentration profiles were determined by a validated HPLC analytical method using fluorescence detection. MXD has an adequate pattern of absorption, based on the low residual concentrations found in the injection site area at all sampling intervals. Muscle samples showed the lowest MXD concentrations throughout the study period. The highest MXD concentrations at all sampling times were measured in the adipose tissue, indicating that fat is a target tissue for MXD. MXD concentrations in all of the tissues analyzed were below the accepted maximum limit of residue at 21 days post-treatment.

Adipose Tissue↗

PubMed2000

Nutritional condition affects the hepatic antioxidant systems in steers.

The objectives of this study were to evaluate the activity of antioxidant systems in the hepatic tissues of steers experimentally subjected to a restricted diet. Hence, the activities of superoxide dismutase (SOD) and reduced glutathione (GSH) and lipid peroxide levels were measured. Nine male Holstein steers were used. They were separated in two groups: three steers in group 1 (control) and six steers in group 2, which were subjected to a restricted diet that covered only 60% of the maintenance requirements. After 30 days, the animals in both groups were killed and studies were completed. Both the CuZn-SOD and the glucose-6-phosphate dehydrogenase activities were significantly decreased (p < 0.05) in group 2, reaching 68% and 60%, respectively, of the concentrations found in group 1. The concentration of GSH in group 2 was 6.71+/-0.9 nmol/mg protein, which was significantly lower (p < 0.01) than that of the controls, 25.7+/-2.4 nmol/mg protein. In addition, the lipid peroxide levels were significantly increased (p < 0.01) in group 2, being 50-60% higher than that in group 1. These results showed that the poor nutritional status caused modifications to the enzymatic antioxidant systems, with a lower ability to reduce oxidative compounds and a state of lipid peroxidation.

Animal Feed↗

PubMed2000

Enantioselective liver microsomal sulphoxidation of albendazole in cattle: effect of nutritional status.

1. The enantioselective liver microsomal sulphoxidation of the benzimidazole anthelmintic, albendazole (ABZ), by cattle liver microsomes has been investigated. The influence of nutritional condition on this biotransformation process was also characterized. 2. ABZ was oxidized to its sulphoxide metabolite (ABZSO) in a NADPH concentration-dependent reaction and the (+) and (-) ABZSO enantiomers formed were identified. 3. Vmax (0.27 nmol ABZSO formed per min x mg(-1) microsomal protein) and Km (15.10 microM) for ABZ sulphoxidation by cattle liver microsomes were obtained. Different Vmax (0.11 and 0.16 nmol x min(-1) x mg(-1)) and Km (9.40 and 26.70 microM) characterized the enantioselective formation of (+) and (-) ABZSO antipodes, respectively. 4. Free fatty acid (FFA) concentrations and beta-hydroxybutyrate concentrations (beta-OHB) in serum and liver homogenates were significantly higher in feed-restricted (poor nutritional condition) compared with control animals in an optimal nutritional status. Serum protein concentrations and liver cytosolic glucose 6-phosphate dehydrogenase (G6PD) activity were significantly lower in the feed-restricted compared with control calf. 5. Animal nutritional condition affected the pattern of ABZ sulphoxidation. A higher Km for (total) ABZSO and (+) ABZSO production was observed in the calf subjected to a period of undernutrition. 6. A nutritionally induced impairment in the affinity of microsomal mixed-function oxidases responsible of ABZ oxidation may be responsible for the observed changes in the liver microsomal sulphoxidation of ABZ in the feed-restricted calf. Furthermore, undernutrition may affect primarily the FMO-mediated formation of (+) ABZSO. These in vitro observations agree with the changes observed in vivo following the administration of ABZ to the calf subjected to a dietary restriction.

Albendazole↗