Lack of sex-influence on the in vitro metabolism of ivermectin by hepatic microsomal preparations from cattle.
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Animals↗
Biomedical subjects
J F Sutra
Publications and source records attributed to J F Sutra.
Some pharmacokinetic parameters of eprinomectin in goats following pour-on administration.
Some pharmacokinetic parameters of eprinomectin were determined in goats following topical application at a dose rate of 0.5 mg/kg. The plasma concentration versus time data for the drug were analysed using a one-compartment model. The maximum plasma concentration of 5.60+/-1.01 ng/ml occurred 2.55 days after administration. The area under the concentration-time curve (AUC) was 72.31+/-1.15 ng day/ml and the mean residence time (MRT) was 9.42+/-0.43 days. Thus, the systemic availability of eprinomectin to goats was significantly lower than that for cows. The low concentration of eprinomectin in the plasma of goats suggests that the pour-on dose of 0.5 mg/kg would be less effective in this species than in cows. Further relevant information about the optimal dosage and residues in the milk of dairy goats is needed before eprinomectin should be used in this species.
Administration, Topical↗
Comparison of the pharmacokinetics of moxidectin (Equest) and ivermectin (Eqvalan) in horses.
A study was undertaken in order to evaluate and compare plasma disposition kinetic parameters of moxidectin and ivermectin after oral administration of their commercially available preparations in horses. Ten clinically healthy adult horses, weighing 390-446 kg body weight (b.w.), were allocated to two experimental groups of five horses. Group I was treated with an oral gel formulation of moxidectin (MXD) at the manufacturers recommended therapeutic dose of 0.4 mg/kg bw. Group II was treated with an oral paste formulation of ivermectin (IVM) at the manufacturers recommended dose of 0.2 mg/kg b.w. 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 HPLC with fluorescence detection. Computerized kinetic analysis was carried out. The parent molecules were detected in plasma between 30 min and either 30 (IVM) or 75 (MXD) days post-treatment. Both drugs showed similar patterns of absorption and no significant difference was found for the time corresponding to peak plasma concentrations or for absorption half-life. Peak plasma concentrations (Cmax) of 70.3+/-10.7 ng/mL (mean +/- SD) were obtained for MXD and 44.0+/-23.1 ng/mL for IVM. Moreover, the values for area under concentration-time curve (AUC) were 363.6+/-66.0 ng x d/mL for the MXD treated group, and 132.7+/-47.3 ng x d/mL for the IVM treated group. The mean plasma residence times (MRT) were 18.4+/-4.4 and 4.8+/-0.6 days for MXD and IVM treated groups, respectively. The results showed a more prolonged residence of MXD in horses as demonstrated by a four-fold longer MRT than for IVM. The longer residence and the higher concentrations found for MXD in comparison to IVM could possibly explain a more prolonged anthelmintic effect. It is concluded that in horses the commercial preparation of MXD presents a pharmacokinetic profile which differs significantly from that found for a commercial preparation of IVM. To some extent these results likely reflect differences in formulation and doses.
Administration, Oral↗
Moxidectin in cattle: correlation between plasma and target tissues disposition.
The time of parasite exposure to active drug concentrations determines the persistence of the antiparasitic activity of endectocide compounds. This study evaluates the disposition kinetics of moxidectin (MXD) in plasma and in different target tissues following its subcutaneous (s.c.) administration to cattle. Eighteen male, 10-month old Holstein calves weighing 120-140 kg were subcutaneously injected in the shoulder area with a commercially available formulation of MXD (Cydectin 1%, American Cyanamid, Wayne, NJ, USA) at 200 micrograms/kg. Two treated calves were killed at each of the following times post-treatment: 1, 4, 8, 18, 28, 38, 48, 58 and 68 days. Abomasal and small intestine mucosal tissue and fluids, bile, faeces, lung, skin and plasma samples were collected, extracted, derivatized and analysed to determine MXD concentrations by high performance liquid chromatography (HPLC) with fluorescence detection. MXD was extensively distributed to all tissues and fluids analysed, being detected (concentrations > 0.1 ng/g; ng/mL) between 1 and 58 days post-treatment. MXD peak concentrations were attained during the first sampling day. MXD maximum concentration (Cmax) values ranged from 52.9 (intestinal mucosa) up to 149 ng/g (faeces). The mean residence time (MRT) in the different tissues and fluids ranged from 6.8 (abomasal mucosa) up to 11.3 (bile) days. MXD concentrations in abomasal and intestinal mucosal tissue were higher than those detected in plasma; however, there was a high correlation between MXD concentrations observed in plasma and those detected in both gastrointestinal mucosal tissues. MXD concentrations were markedly greater in the mucosa than in its respective digestive fluid (P < 0.01). MXD concentrations in skin were higher than those found in plasma (P < 0.01). Drug concentrations recovered in the dermis were greater than those detected in the hypodermal tissue (P < 0.05). Large concentrations of MXD were excreted in bile and faeces. These findings may contribute to an understanding of the relationship between the kinetic behaviour and the persistence of the antiparasite activity of MXD against different ecto-endoparasites in cattle.
Abomasum↗
Persistence of ivermectin in plasma and faeces following administration of a sustained-release bolus to cattle.
Six calves (weight 210 to 230 kg) were dosed with an intra-ruminal slow-release bolus prepared to deliver ivermectin at a low daily dosage for 135 days. Ivermectin concentrations in jugular blood 160 days post-treatment were determined by high performance liquid chromatography (HPLC) using fluorescence detection. Ivermectin plasma concentrations increased gradually to achieve the steady-state concentration (20 ng ml(-1)) at approximately four days post-treatment, which was maintained for 120 days. The ivermectin peak plasma concentration (28.5 ng ml(-1)) was attained at 15 days post-administration of the bolus. The faecal ivermectin concentration rose to a maximal concentration of 4.1 microg g(-1) at four days post-treatment, dropping to a steady-state concentration of around 1.18 microg g(-1) which was maintained up to 120 days post-treatment. Ivermectin was detected in both plasma (0.05 ng ml(-1)) and faeces (2.67 ng g(-1)) up to 160 days. The high levels of ivermectin recovered in faeces indicate that a large proportion of the dose released by the bolus (80 to 90 per cent) is excreted in faeces.
Animals↗
Pharmacokinetics of moxidectin and doramectin in goats.
The pharmacokinetic behaviour of doramectin after a single subcutaneous administration and moxidectin following a single subcutaneous or oral drench were studied in goats at a dosage of 0.2 mg kg(-1). The drug plasma concentration-time data were analysed by compartmental pharmacokinetics and non-compartmental methods. Maximum plasma concentrations of moxidectin were attained earlier and to a greater extent than doramectin (shorter t(max) and greater C(max) and AUC than doramectin). MRT of doramectin (4.91 +/- 0.07 days) was also significantly shorter than that of moxidectin (12.43 +/- 1.28 days). Then, the exposure of animals to doramectin in comparison with moxidectin was significantly shorter. The apparent absorption rate of moxidectin was not significantly different after oral and subcutaneous administration but the extent of absorption, reflected in the peak concentration (C(max)) and the area under the concentration-time curve (AUC), of the subcutaneous injection (24.27 +/- 1.99 ng ml(-1) and 136.72 +/- 7.35 ng d ml(-1) respectively) was significantly greater than that of the oral administration (15.53 +/- 1.27 ng ml(-1) and 36.72 +/- 4.05 ng d ml(-1) respectively). The mean residence time (MRT) of moxidectin didn't differ significantly when administered orally or subcutaneously. Therefore low oral bioavailability and the early emergence of resistance in this minor species may be related. These results deserve to be correlated with efficacy studies for refining dosage requirements of endectocides in this species.
Administration, Oral↗
Pharmacokinetics of eprinomectin in plasma and milk following topical administration to lactating dairy cattle.
The pharmacokinetics and mammary excretion of eprinomectin were determined in cattle following topical administration at a dose rate of 0.5 mg kg(-1). The kinetics of plasma and milk concentrations were analysed using a one-compartment model. The maximum plasma concentration of 43.76 ng ml(-1)occurred 2.02 days post administration, and the mean residence time was 4.16 days. Eprinomection was detected in the milk at the first sampling time and thereafter for at least 15 days. Comparison of the milk and plasma data demonstrated the parallel disposition of the drug in the milk and plasma with a milk / plasma concentration ratio of 0. 102+/-0.048. The amount of drug recovered in the milk during this period was 0.109% +/- 0.038 of the total administered dose. This very low extent of mammary excretion resulted in low concentrations of eprinomectin in milk. This supports the permitted use in lactating cattle, as the maximum level of residue in milk did not exceed the maximum acceptable limit of 30 ng ml(-1).
Administration, Topical↗
Determination of eprinomectin in plasma by high-performance liquid chromatography with automated solid phase extraction and fluorescence detection.
A method is described for the determination of eprinomectin in plasma using high-performance liquid chromatography with fluorescence detection (excitation and emission wavelengths 355 and 465 nm, respectively). The fluorescent derivative was obtained by a condensation reaction with trifluoroacetic anhydride and N-methylimidazole. The method employs 1 ml plasma samples and gives linear calibration graphs (r = 0.999) over the concentration range studied (0.5-50 ng ml-1). Solid extraction using the benchmate procedure was used for sample preparation. This method permits the determination of eprinomectin at levels as low as 0.1 ng ml-1 and is suitable for the pharmacokinetic study of eprinomectin in animals.
Animals↗
Identification of human and rabbit cytochromes P450 1A2 as major isoforms involved in thiabendazole 5-hydroxylation.
This report characterized one of the major cytochrome P450 isozyme involved in thiabendazole metabolism. This study was undertaken by using both cultured rabbit hepatocytes treated or not with drugs known to specifically induced various cytochromes P450 isoenzymes (i.e., P450 1A1/2 by beta-naphthoflavone, P450 2B4 by phenobarbital, P450 3A6 by rifampicine and P450 4A by clofibrate) and human liver (THLE-5) and bronchial (BEAS-2B) epithelial cells expressing or not the major constitutive human cytochromes P450 (i.e., CYP1A2, 2A6, 2B6, 2C9, 2D6, 2E1 or 3A4). Only hepatocytes exposed to beta-naphthoflavone and clofibrate significantly metabolized thiabendazole to 5-hydroxythiabendazole. Extensive biotransformation of this anthelmintic only occurred in human cells expressing CYP1A2. Moreover, experiments performed on rabbit preparations showed good correlations between thiabendazole 5-hydroxylase activity and both ethoxyresorufin and methoxyresorufin O-dealkylase activities. Thus, CYP1A2 is a major isoenzyme involved in thiabendazole 5-hydroxylation.
Animals↗
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 micrograms/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 (t1/2ab) = 1.32 h) than those of IVM (t1/2ab = 39.2 h) and DRM (t1/2ab = 56.4 h). MXD peak plasma concentration (Cmax) was reached significantly earlier (8.00 h) compared to those of IVM and DRM (4-6 days post-treatment). There were no differences on Cmax 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.
Animals↗
Pharmacokinetics of ivermectin in the camel (Camelus dromedarius).
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Animals↗
Matrix solid-phase dispersion technique for the determination of moxidectin in bovine tissues.
An HPLC method has been developed for the determination of moxidectin in bovine tissues. The extraction and clean-up procedure is based on the matrix solid-phase dispersion technique. Control and moxidectin-fortified bovine tissue samples (0.25 g) are blended with octadecyl (C18 end-capped) packing material. A column made from the C18-bovine tissue blend is washed with hexane (2 ml); when all the hexane has eluted, an Alumina-B SPE cartridge is attached below the C18-tissue column and, after washing, moxidectin is eluted with methanol (6 ml). Moxidectin is derivatized and determined by HPLC with fluorescence detection. The recovery from fortified samples was greater than 80% in the concentration range 1-100 ng g-1 of tissue. This method permits the determination of moxidectin at levels as low as 1 ng g-1 (1 ppb).
Animals↗
Major involvement of rabbit liver cytochrome P4501A in thiabendazole 5-hydroxylation.
1. Thiabendazole is a widely used food preservative and anthelmintic drug for breeding animal species. In order to characterize precisely the cytochrome P450 isozyme(s) involved in its major route of metabolism, a rapid and sensitive spectrofluorimetric method was developed for the simultaneous determination of thiabendazole and its main hepatic metabolite 5-hydroxythiabendazole. 2. The kinetics of thiabendazole 5-hydroxylation were determined in microsomal preparations from control rabbits or animals previously treated with either beta-naphthoflavone, isosafrole, phenobarbital, rifampicin or clofibrate. These treatments led to specific induction of CYP1A1, 1A2, 2B4, 3A6 and 4A1 respectively. 3. By considering this panel of characterised microsomal preparations, only those obtained from BNF-treated rabbits exhibited an increase in thiabendazole 5-hydroxylase activity Ethoxyresorufin O-deethylation in these microsomes was solely inhibited by thiabendazole. These argue for a specific involvement of the CYP1A subfamily. 4. In the CYP1A subfamily, CYP1A2 appears to be responsible for basal 5-hydroxylation and further unidentified metabolism of thiabendazole in control livers. However, the major involvement of CYP1A1 is supported by the following characteristics of 5-hydroxylation of thiabendazole: (1) the correlation with CYP1A1 expression and (2) the inhibition by ellipticine and not by furafylline, inhibitors of CYP1A1 and CYP1A2 respectively. 5. All these data demonstrated that the rabbit cytochrome P4501A is predominantly involved in thiabendazole 5-hydroxylation which has been suspected to be critical in terms of safety of the parent drug.
Animals↗
Plasma profile study of moxidectin in a cow and its suckling calf.
The plasma concentration of moxidectin, a macrocyclic lactone endectocide, was investigated in a cow and its suckling calf, using a new chemical assay, following subcutaneous injection (0.2 mg/kg) in the cow. The most striking result was the persistence of moxidectin in the plasma of the cow (mean residence time: 25.66 days). Moxidectin was also detected in the plasma of the calf as a result of the excretion of the drug in the cow's milk and its ingestion by the calf. The cow and calf plasma concentrations and pharmacokinetic parameters showed parallel disposition of the drug. The suckling calf received about 5% of the dose from the cow via the milk.
Animals↗
Determination of moxidectin in plasma by high-performance liquid chromatography with automated solid-phase extraction and fluorescence detection.
Moxidectin is a newly developed potent anthelmintic agent with a high potency although present at very low concentration in cattle plasma. A method is described for the determination of moxidectin in plasma using high-performance liquid chromatography with fluorescence detection (excitation and emission wavelengths 383 and 447 nm, respectively). The fluorescent derivative was obtained by a dehydrative reaction with trifluoroacetic anhydride and N-methylimidazole. The method employs 1-ml plasma samples and has linear calibration graphs (r = 0.997) over the concentration range studied, i.e., 0.1-10 ng/ml. Solid-phase extraction using the Benchmate procedure was used for sample preparation. Recoveries at low concentrations (0.1-10 ng/ml) were higher than 75%. The limit of quantification was 0.1 ng/ml (C.V. 6.95%). The method is suitable for the pharmacokinetic study of moxidectin after subcutaneous administration to cows.
Animals↗
Fasciola hepatica: mebendazole and thiabendazole pharmacokinetics in sheep.
Pharmacokinetics of the two anthelmintic drugs mebendazole and thiabendazole were determined in sheep before and 4, 8, 13, 19, and 25 weeks after an infestation of animals by an oral administration of 150 metacercariae of Fasciola hepatica. The parasitic pathology was ascertained by the increase in plasma enzyme activities of glutamate dehydrogenase and gamma-glutamyltransferase. After oral administration of mebendazole (25 mg.kg-1), the parent drug and especially its reduced metabolite were present in plasma of animals. A significant 1.5- to 2.7-fold increase in the mean residence time occurred by Weeks 13 to 25 postinfection. This change was related to decreases in both the elimination from the pharmacokinetic compartment representing the reduced metabolite and the area under the curve of plasma metabolite concentration versus time. A 59% decrease in MBZ reduction was demonstrated in liver microsomes prepared from 12-week-infected sheep. This reductase activity was characterized by NADPH dependency and a pH peak activity of 6.0 and was competitively inhibited by daunomycin. In sheep receiving a 50 mg.kg-1 oral dose of thiabendazole, fascioliasis provoked only decreased plasma concentrations of the metabolite 5-hydroxythiabendazole by Weeks 4 to 25 postinfection. This change parallels an increase in urinary excretion of free metabolite but this is of minor significance in the general fate of the drug because of the prevalence of excretion as conjugates. In summary, fascioliasis appears to have more of an effect on the pharmacokinetics of mebendazole, a drug intensively metabolized by the liver into a metabolite present at high concentrations in the plasma of animals and humans.
Administration, Oral↗
Consequences of challenge infections with Fasciola hepatica on rat liver P450-dependent metabolism of sex hormones.
The effect of single or repetitive fluke-infections on rat liver steroid hormone metabolism was studied. Fascioliasis was induced by oral administration of 20 metacercariae of Fasciola hepatica to rats, by week-6 (mono-infected) or 12 and 6 (bi-infected), or 12, 9 and 6 (tri-infected) before killing. Total microsomal cytochrome P450 and P450 isoenzymes were measured spectrophotometrically and by Western-blot analysis, respectively. Progesterone and testosterone metabolism were quantified by normal phase high performance liquid chromatography. In control rats, progesterone and testosterone were mainly converted to 2 alpha- and 16 alpha-hydroxymetabolites. In the liver of mono-infected rats, hepatic cytochrome P450 was significantly decreased by 36-64% whereas the expression of all investigated isoenzymes was decreased by 36-82% with the exception of the unchanged P4502E1. 16 alpha- and 2 alpha-hydroxylations of progesterone and testosterone were significantly decreased by 50-90%, these decreases were correlated with those of P4502B1/2 and P4502C11 isoenzymes, respectively. In bi- and tri-infected rats, steroid hormones were metabolized similarly to control rats. The return of steroid drug metabolizing enzyme activities to control level could be related to the immune response associated to the development of the animal resistance to the parasitic infection.
Animals↗
Determination of aditoprim and its oxidative metabolites in plasma and microsomal incubation mixtures by high-performance liquid chromatography.
A high-performance liquid chromatographic method is presented for the determination of aditoprim (ADP) and its two oxidative metabolites in biological fluids including sheep plasma and the incubation medium of liver microsomes. The compounds were separated using a highly deactivated C18 column; the mobile phase consisted of an 0.05 M phosphate buffer (pH 6) and acetonitrile in a ratio of 90:10 (v/v). The eluate was quantified by ultraviolet detection at 230 nm. Calibration curves were linear from 0.25 to 5 micrograms/ml. The limit of detection was 0.05 microgram/ml. In an in vivo kinetic study in sheep, N-monodesmethyl-ADP and N-didesmethyl-ADP appeared to be equally important metabolites. In contrast, in in vitro metabolism studies using liver microsomes from different animal species including sheep, N-didesmethyl-ADP was formed predominantly.
Animals↗