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J F Sutra

Publications and source records attributed to J F Sutra.

At least 19 recordsLinked to original sources
PubMed2006

Eprinomectin in dairy zebu Gobra cattle (Bos indicus): plasma kinetics and excretion in milk.

The pharmacokinetics and mammary excretion of eprinomectin were determined in zebu Gobra following topical administration of 0.5 mg kg(-1). The kinetics of plasma and milk was analysed using a one-compartment model. The maximum plasma concentration of 8.83+/-2.15 ng ml(-1) occurred 1.30 days post-administration. The area under the plasma concentration-time curve was 30.63+/-5.56 ng day(-1) ml(-1) and the mean residence time was 3.38+/-0.60 days. Eprinomectin was detected in milk at the first sampling time and thereafter for at least 8 days. The systemic availability of eprinomectin was significantly lower than that for other breeds of cattle. Comparison of the milk and plasma data demonstrated the parallel disposition of the drug in the milk and plasma with a milk/plasma ratio of 0.094. The very low extent of mammary excretion supports the permitted use of eprinomectin in lactating zebu Gobra.

Administration, Topical↗
PubMed2006

The interaction between moxidectin and MDR transporters in primary cultures of rat hepatocytes.

The interaction of moxidectin (a macrocyclic lactone, ML) with P-glycoprotein (P-gp), multidrug resistance associated proteins (MRPs) and breast cancer resistance protein (BCRP) was studied in primary cultures of rat hepatocytes by measuring the intracellular accumulation of [14C]-moxidectin over 72 h in the presence of specific inhibitors: for P-gp, verapamil (10 microM); for MRPs, MK571 (100 microM), indomethacin (10 microM) and probenecid (3.8 mM); and for BCRP, fumitremorgin C (5 microM). The P-gp and MRP inhibitors increased significantly (P < 0.01) by 48.7%, 49.8%, 49.9% and 57.2% the area under the time-intracellular concentration curve (AUC) of moxidectin in rat hepatocytes, while the BCRP inhibitor, fumitremorgin C, had no effect on the AUC compared with the control. In addition, the mRNAs of all the drug transporters studied were detected in rat hepatocytes from 0 to 72 h. Using this cellular model it has been shown that MRP inhibitors increase moxidectin intracellular concentrations to a similar extent as the P-gp inhibitor. The identification of all the transporters that interact with MLs remains a challenge, which currently concerns several important therapeutic fields.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Fumagillin, a new P-glycoprotein-interfering agent able to modulate moxidectin efflux in rat hepatocytes.

We have tested the ability of two compounds licensed in veterinary medicine: fumagillin and diminazene diaceturate to increase intracellular moxidectin quantity in rat hepatocytes. These compounds significantly increased the quantity of 14C-moxidectin (expressed as area under the time curve concentrations) in cultured rat hepatocytes by 44% and 65% for diminazene and fumagillin treatments respectively. In addition, we have tested these drugs for their interference with P-glycoprotein (P-gp) function in porcine kidney epithelial cells transfected with murine mdr1a (Mdr1a-LLCPK1). We examined the intracellular accumulation of rhodamine 123 (Rho 123) as a functional test to evaluate the effects of these two drugs on P-gp activity. In this model, only fumagillin led to a marked intracellular accumulation of Rho 123. After transforming the data to express the results as a percentage of the accumulation in the presence of the P-gp inhibitor valspodar (VSP), the maximal Rho 123 accumulation was 47% of that with VSP for 100 microm fumagillin. The EC50, the concentration needed to determine 50% of the maximal effect was 34 microm. Fumagillin interacts with P-gp function and appears as a promising compound among registered drugs available, which may optimize the therapeutic use of macrocyclic lactones (MLs).

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

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.

Animals↗
PubMed2004

Pharmacokinetics of selamectin in dogs after topical application.

Some pharmacokinetic parameters of selamectin were determined in male (n = 5) and female (n = 5) Beagle dogs following a topical application at a dose rate of 6 mg/kg. The plasma concentration versus time data for the drug were analysed using a one-compartment model. The maximum plasma concentrations of 12.72 +/- 5.13 ng/ml for males and 22.65 +/- 11.95 ng/ml for females occurred around 5 days after administration. The area under the concentration-time curve (AUC) was 192.08 +/- 63.85 ng.day/ml for males and 370.97 +/- 146.87 ng.day/ml for females. The mean residence time was the same in males and females (12.55 days). This study reveals a sex-influence on the disposition of selamectin in the plasma of dogs, which implies that further information will be needed for correlation with efficacy studies in dogs.

Administration, Topical↗
PubMed2003

Pharmacokinetics of ivermectin in the yak (Bos grunniens).

The yak (Bos grunniens) belongs to the cattle family Bovidae and lives in the mountains of China and adjacent areas. Due to the physiological adaptations of yak to its environment and the lack of data, the ivermectin pharmacokinetic was studied following a single subcutaneous dose at the recommended dose for cattle (0.2 mg kg(-1)). The observed peak plasma concentration (Cmax) was 48.93 ng ml(-1) and the time to reach Cmax (Tmax) was 0.73 day. These results show a faster rate of absorption than in cattle. The values for the absorption half-life (t(1/2a)), the distribution half-life (t(1/2alpha)) and the terminal half-life (t(1/2beta)) were 0.31, 0.74 and 4.82 days, respectively. The calculated area under the concentration-time curve (AUC) was 146.2 ng day ml(-1) and the mean residence time (MRT) was 3.57 days. The availability of ivermectin appears low in yaks in comparison to cattle but equivalent to that reported in horses and is likely to be due to physiological characteristics of this species.

Absorption↗
PubMed2003

Enhancement of moxidectin bioavailability in lamb by a natural flavonoid: quercetin.

Moxidectin is an antiparasitic drug widely used in cattle, sheep and companion animals. Due to the involvement of P-glycoprotein (P-gp) and cytochrome P450 3A in the metabolism of moxidectin, we studied the influence of various P-gp interfering agents (ivermectin, quercetin and ketoconazole) on the metabolism of 14C moxidectin in cultured rat hepatocytes over 72 h. This in vitro study allowed selection of compounds which are able to increase the moxidectin bioavailability in lambs. From this, the modulation of moxidectin pharmacokinetics in plasma of lambs was studied after co-administration of 0.2 mg kg(-1) moxidectin (subcutaneously (SC)) and 0.2 mg kg(-1) ivermectin (SC), or 10 mg kg(-1) quercetin (SC), or 10 mg kg(-1) ketoconazole (orally). Ivermectin and quercetin increased significantly the quantity of 14C moxidectin in the rat hepatocytes. Ketoconazole co-administration led to a higher concentration of moxidectin in the rat hepatocytes. In vivo, only quercetin was able to modify the pharmacokinetics of moxidectin in plasma of lambs by increasing significantly the area under the plasma concentration-time curve. This study allowed the use of a natural agent, quercetin, to improve the bioavailability of moxidectin.

Animals↗
PubMed2002

Eprinomectin in goat: assessment of subcutaneous administration.

Eprinomectin is only available as a topically applied anthelmintic for dairy cattle. To determine whether eprinomectin can be administered in the goat as an injectable formulation, it was subcutaneously delivered to six goats and measured in the plasma at different times after administration. The area under the concentration-time curve (AUC) reported after subcutaneous administration of 0.2 mg kg(-1) eprinomectin (68.5+/-23.2 ng day(-1) ml(-1)) was similar to the AUC previously reported for goats after a pour-on administration of 0.5 mg kg(-1) eprinomectin. Thus, our results clearly show that subcutaneous administration is 2.5 times more effective than pour-on administration, in terms of amount of drug present in the organism. This work should encourage the development of a subcutaneous formulation of eprinomectin and should contribute to defining optimal therapeutic conditions for goat anthelmintic treatment.

Animals↗
PubMed2001

Eprinomectin in dairy goats: dose influence on plasma levels and excretion in milk.

The plasma levels and milk excretion of eprinomectin were determined in goats following topical application at doses of 0.5 mg kg(-1) and 1.0 mg kg(-1). The area under the concentration-time curve (AUC) was 2 times lower for 0.5 mg kg(-1) (8.24 +/- 3.50 ng day(-1) ml(-1)) than for 1.0 mg kg(-1) (15.68 +/- 8.84 ng day(-1) ml(-1)), suggesting that the pharmacokinetics of eprinomectin in goats is dose independent. The bioavailability of eprinomectin in lactating compared with non-lactating goats is low. This is probably due to the physiological status of dairy animals, which present a marked decrease in body fat. Comparison of the eprinomectin concentrations in the milk and plasma demonstrated a parallel disposition of the drug with a milk-to-plasma ratio of 0.10-0.25. The amount of drug recovered in the milk was 0.3-0.5% of the total administered dose. In all cases, the maximum level of residue in milk remained below the maximum acceptable level of 30 ng ml(-1) permitted in lactating cattle.

Administration, Topical↗
PubMed2001

In vitro metabolism of moxidectin in Haemonchus contortus adult stages.

We studied the implication of cytochrome P450 enzymes in the in vitro metabolism of moxidectin (MXD) in homogenates of Haemonchus contortus adult stages (susceptible isolate, Weybridge, UK). After homogenisation in a phosphate buffer, 2 ml of homogenates (equivalent to 1 g of nematodes) were incubated with 5 microg [14C] MXD at 37 degrees C for 24 h. MXD and its metabolites were separated by HPLC with radiodetection on-line. Only one metabolite was detected and its production was inhibited by carbon monoxide. This result demonstrates that the cytochrome P450 system is implicated in the metabolisation of MXD in H. contortus susceptible to milbemycin. Furthermore, this metabolite did not match those previously described in vertebrates.

Animals↗
PubMed2001

In vitro metabolism of 14C-moxidectin by hepatic microsomes from various species.

Moxidectin is an antiparasitic drug widely used in cattle, sheep and companion animals. No data were available on its metabolism in wild species or in monogastrics. The in vitro metabolism of 14C-moxidectin was studied using hepatic microsomes from several different species: cow (Bos taurus). sheep (Ovis ovis), goat (Capra hircus), deer (Cervus dama), rat (Rattus norvegicus), pig (Sus scrofa and rabbit (Oryctolagus cuniculus). After separation and quantification by HPLC, the extent of metabolism of 14C-moxidectin was greatest with microsomes from sheep (32.7%) as compared to those from cows (20.6%), deer (15.4%), goats (12.7%). rabbits (7.0%) or rats (3.0%). The least metabolism occurred with microsomes from pigs. with 0.8% of total detected metabolites. A C29 monohydroxymethyl metabolite was detected in the greatest amounts. providing 0.4% out of the total detected radioactivity in pigs and 19.3% in sheep. In addition, the importance of P450 3A in the metabolism of 14C-moxidectin was confirmed by using in vivo induced P450 in combination with various P450 inhibitors.

Animals↗
PubMed2001

Influence of verapamil on the efflux and metabolism of 14C moxidectin in cultured rat hepatocytes.

Moxidectin (MOX) is an antiparasitic drug widely used in cattle, sheep and companion animals. As a result of the implication of cytochrome P450 3 A in the metabolism of MOX and the role of competitor substrates of P-glycoprotein (Pgp) in modification of the bioavailability of endectocides, we studied the influence of verapamil (a multidrug-resistance reversing agent) on the metabolism of 14C moxidectin in cultured rat hepatocytes over 72 h. The metabolism of MOX remained low: 10.79 +/- 1.99% of the total 14C moxidectin for the main detected metabolite in verapamil-treated cells and 7.17 +/- 0.74% for the control cells after 24 h. The main detected metabolite in rat hepatocytes was the same as that detected in rat hepatic microsomes (the C29 monohydroxymethyl metabolite). Verapamil increased the quantity of MOX in the cells after 24, 48 and 72 h. Examination of the Area Under the concentration time Curve (AUC) of the main detected metabolite revealed a significant increase in the exposure of cells to MOX after verapamil treatment throughout the experiment. It is hypothesized that verapamil interfered with MOX as a substrate for Pgp during the initial incubation period. After this initial interaction, verapamil metabolites were able to interfere with Pgp. This experiment demonstrated the implication of Pgp in the transport of MOX and allowed prediction of the drug-drug interactions which might modify the bioavailability of endectocides.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Milk kinetics of moxidectin and doramectin in goats.

The milk kinetics of doramectin after a single subcutaneous administration and moxidectin following a single subcutaneous or oral drench were studied in goats (n = 15) at a dosage of 0.2 mg kg(-1). Doramectin could be detected in the milk for 21.0+/-2.9 days after subcutaneous treatment, and the total fraction of the dose recovered from the milk was estimated to be 2.9+/-0.88 per cent. Moxidectin, after either oral or subcutaneous administration, could be detected in the milk up to day 40 and the total fractions of the dose recovered from the milk were estimated to be 5.7+/-1.04 per cent and 22.53+/-1.09 per cent, respectively. The mean residence time after subcutaneous administration indicated that moxidectin delivered by the milk persists three times longer than doramectin; furthermore, the total fraction of the dose of moxidectin recovered from the milk was 7.7 times higher than that of doramectin.

Administration, Oral↗
PubMed2001

Faecal excretion profile of moxidectin and ivermectin after oral administration in horses.

A study was undertaken to evaluate and compare faecal excretion of moxidectin and ivermectin in horses after oral administration of commercially available preparations. Ten clinically healthy adult horses, weighing 390-446 kg body weight (b.w.), were allocated to two experimental groups. Group I was treated with an oral gel formulation of moxidectin at the manufacturer's recommended therapeutic dose of 0.4 mg/kg b.w. Group II was treated with an oral paste formulation of ivermectin at the recommended dose of 0.2 mg/kg b.w. Faecal samples were collected at different times between 1 and 75 days post-treatment. After faecal drug extraction and derivatization, samples were analysed by High Performance Liquid Chromatography using fluorescence detection and computerized kinetic analysis. For both drugs the maximum concentration level was reached at 2.5 days post administration. The ivermectin treatment groups' faecal concentrations remained above the detectable level for 40 days (0.6 +/- 0.3 ng/g), whereas the moxidectin treatment group remained above the detectable level for 75 days (4.3 +/- 2.8 ng/g). Ivermectin presented a faster elimination rate than moxidectin, reaching 90% of the total drug excreted in faeces at four days post-treatment, whereas moxidectin reached similar levels at eight days post-treatment. No significant differences were observed for the values of maximum faecal concentration (C(max)) and time of C(max)(T(max)) between both groups of horses, demonstrating similar patterns of drug transference from plasma to the gastrointestinal tract. The values of the area under the faecal concentration time curve were slightly higher in the moxidectin treatment group (7104 +/- 2277 ng.day/g) but were not significantly different from those obtained in the ivermectin treatment group (5642 +/- 1122 ng.day/g). The results demonstrate that although a 100% higher dose level of moxidectin was used, attaining higher plasma concentration levels and more prolonged excretion and gut secretion than ivermectin, the concentration in faeces only represented 44.3+/- 18.0% of the total parental drug administered compared to 74.3 +/- 20.2% for ivermectin. This suggests a higher level of metabolization for moxidectin in the horse.

Administration, Oral↗
PubMed2000

Evidence for cytochrome P4501A2-mediated protein covalent binding of thiabendazole and for its passive intestinal transport: use of human and rabbit derived cells.

Thiabendazole (TBZ), an anthelmintic and fungicide benzimidazole, was recently demonstrated to be extensively metabolized by cytochrome P450 (CYP) 1A2 in man and rabbit, yielding 5-hydroxythiabendazole (5OH-TBZ), the major metabolite furtherly conjugated, and two minor unidentified metabolites (M1 and M2). In this study, exposure of rabbit and human cells to 14C-TBZ was also shown to be associated with the appearance of radioactivity irreversibly bound to proteins. The nature of CYP isoforms involved in this covalent binding was investigated by using cultured rabbit hepatocytes treated or not with various CYP inducers (CYP1A1/2 by beta-naphthoflavone, CYP2B4 by phenobarbital, CYP3A6 by rifampicine, CYP4A by clofibrate) and human liver and bronchial CYP-expressing cells. The covalent binding to proteins was particularly increased in beta-naphthoflavone-treated rabbit cells (2- to 4-fold over control) and human cells expressing CYP1A2 (22- to 42-fold over control). Thus, CYP1A2 is a major isoenzyme involved in the formation of TBZ-derived residues bound to protein. Furthermore, according to the good correlation between covalent binding and M1 or 5OH-TBZ production, TBZ would be firstly metabolized to 5OH-TBZ and subsequently converted to a chemically reactive metabolic intermediate binding to proteins. This metabolic activation could take place preferentially in liver and lung, the main biotransformation organs, rather than in intestines where TBZ was shown to be not metabolized. Moreover, TBZ was rapidly transported by passive diffusion through the human intestinal cells by comparison with the protein-bound residues which were not able to cross the intestinal barrier. Consequently, the absence of toxicity measured in intestines could be related to the low degree of TBZ metabolism and the lack of absorption of protein adducts. Nevertheless, caution is necessary in the use of TBZ concurrently with other drugs able to regulate CYP1A2, particularly in respect to liver and lung tissues, recognised as sites of covalent-binding.

Animals↗
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↗
PubMed1999

Enhanced absorption of pour-on ivermectin formulation in rats by co-administration of the multidrug-resistant-reversing agent verapamil.

The effect of verapamil, a multidrug-resistance (Mdr)-reversing agent on the absorption of a pour-on formulation of ivermectin was evaluated in rats. Absorption of ivermectin was effectively enhanced (40%) by the presence of verapamil, suggesting that absorption of ivermectin involves Mdr-P-glycoprotein and that verapamil should act as a competitive inhibitor for the transport and extrusion of ivermectin by P-glycoprotein. This hypothesis is consistent with other studies describing verapamil as a blocking agent of P-glycoprotein involved in the efflux of ivermectin in a resistant strain of Haemonchus contortus.

Absorption↗