In vitro Metabolism of 14C-Moxidectin by Hepatic Microsomes from Various Species (original) (raw)
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Journal of the Brazilian Chemical Society, 2016
The widespread use of moxidectin (MOX), a parasiticide used in the sheep breeding, has induced the parasite resistance in Brazilian farms. As a consequence, the farmers often increase the dose and frequency of drug utilization, and disregards safety of meat or milk. In order to establish adequate therapeutic treatment it is necessary to know the pharmacokinetics of the drug in the animal's body. Thus, high performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) method was developed for the determination of MOX in serum lamb. Serum samples were treated with acetonitrile to precipitate proteins. A clean up by dispersive extraction in solid phase (SPE-d), using primary/secondary amine (PSA) and C18 sorbents, followed by freezing was performed. Method validation presented precision (coefficient of variation) and accuracy (recovery%) between 1.7-6.7 and 80.0-107.3%, respectively. The limit of quantification (LOQ) of the method was 2.0 ng mL-1 and a linear response was obtained over a range of 2.0 to 100 ng mL-1. This method was successfully applied to the determination of MOX in serum from suffolk lamb to evaluate the pharmacokinetic profile.
Journal of Pharmaceutical and Biomedical Analysis, 2002
A sensitive and selective high-performance liquid chromatography (HPLC) method is presented for the analysis of moxidectin in human plasma. Solid phase extraction using Oasis ® HLB cartridges is used for sample preparation. The fluorescent derivative is obtained by a dehydrative reaction with trifluoroacetic anhydride and N-methylimidazole. Separation is achieved on a Bondapak C 18 reversed-phase column with a mobile phase composed of tetrahydrafuranacetonitrile-water (40:40:20, v/v/v). Detection is by fluorescence, with excitation at 365 nm and emission at 475 nm. The retention times of moxidectin and internal standard, ivermectin are approximately 10.7 and 18.6 min, respectively. The assay is linear over the concentration range 0.2-1000 ng/ml for moxidectin in human plasma (r =0.9999, weighted by 1/concentration). Recoveries at concentrations 0.2, 400, 1000 ng/ml are 94, 75, and 71%, respectively. The analysis of quality control (QC) samples for moxidectin (0.2, 400, and 1000 ng/ml) demonstrates excellent precision with relative standard deviations of 11.9, 5.7, and 2.7%, respectively (n= 6). The method is accurate with all intra-(n=6) and inter-day (n=18) mean concentrations within (5.0%) from nominal at all QC sample concentrations. Moxidectin was found to be stable after three free-thaw cycles, and with storage at − 20 and − 80°C for 12 weeks. The method is suitable for pharmacokinetic studies of moxidectin after oral administration to humans.
Pharmacokinetics assessment of moxidectin long-acting formulation in cattle
Veterinary Parasitology, 2007
The plasma kinetics disposition of moxidectin following a subcutaneous administration with a long-acting formulation (Cydectin 1 10%, Fort Dodge Animal Health, France) at the recommended dose of 1 mg kg À1 body weight was evaluated in Charolais cattle breed (five females weighing 425-450 kg) for 120 days. Furthermore, its concentration was measured in hair for the same period. After plasma extraction and derivatization, samples were analysed by HPLC with fluorescence detection. Moxidectin was first detected at 1 h after treatment for plasma (2.00 AE 1.52 ng ml À1 ) and at 2 days for hair (446.44 AE 193.26 ng g À1 ). The peak plasma concentration (C max ) was 55.71 AE 15.59 ng ml À1 and 444.44 AE 190.45 ng g À1 for plasma and hair, respectively. The mean calculated time of peak occurrence (T max ) was 3.40 AE 3.36 and 2 days for plasma and hair, respectively. The mean residence time (MRT) was 28.93 AE 2.87 and 13.32 AE 2.48 days for plasma and hair cattle. The area under concentration-time curve (AUC) was 1278.95 AE 228.92 ng day ml À1 and 2663.82 AE 1096.62 ng day g À1 for plasma and hair, respectively. At the last sampling time (120 days), the concentration was 1.91 AE 0.26 ng ml À1 and 0.69 AE 0.52 ng g À1 for plasma and hair, respectively. The bioavailability of this long-acting formulation of moxidectin is similar to that registered after subcutaneous administration of moxidectin in cattle at 0.2 mg kg À1 body weight. For the first time the moxidectin pharmacokinetics parameters in hair after a subcutaneous administration was described. The moxidectin profile concentrations in hair reflected that registered in plasma. The previous studies of efficacy have to be correlated to the extended period of absorption and distribution by the LA formulation due to the fivefold higher dose rate in comparison with the 1% injectable formulation (0.2 mg kg À1 body weight). #
PHARMACOKINETICS OF MOXIDECTIN IN THE SOUTHERN HAIRY-NOSED WOMBAT (LASIORHINUS LATIFRONS)
Journal of Wildlife Diseases, 2011
Sarcoptic mange, caused by Sarcoptes scabiei var. wombati, could be a significant threat to populations of southern hairy-nosed wombats (Lasiorhinus latifrons; SHNW) in Australia. Treatment is currently based on the off-label use of various parasiticidal drugs, with limited clinical efficacy trials. Our primary aim was to determine the pharmacokinetic parameters of a macrocyclic lactone, moxidectin, to assist in the development of effective treatment protocols. Pharmacokinetic parameters were determined in four female SHNW following a single subcutaneous injection of 0.2 mg/kg moxidectin. Blood samples were collected for 38 days following injection (August-September 2008), for analysis using liquid chromatography and tandem mass spectrometry. The mean peak plasma concentration occurred at 13.6 hr, with a mean peak plasma level of 98.6 ng/ml. The mean elimination half-life was 5.03 days, resulting in a mean area under the curve of 377 ng.day/ml. The peak plasma moxidectin concentration was higher than that seen in livestock species but the plasma elimination half-life was shorter. This study suggests that a single injection of 0.2 mg/kg moxidectin may not be sufficient to clear a mange infection in this species.
The influence of parasitism on the pharmacokinetics of moxidectin in lambs
Parasitology Research, 2004
Most pharmacokinetic studies on anthelmintic drugs have been performed on non-parasitized animals. However, it seems likely that the parasite burden could influence the deposition of such drugs. The pharmacokinetics of moxidectin administered orally and by subcutaneous injection was compared in lambs exposed to nematode infection and in parasite naive lambs. Plasma samples were analyzed for moxidectin over 40 days post-treatment. The main pharmacokinetic parameters calculated demonstrated a significant change in drug deposition in infected lambs when compared to controls. The area under the plasma concentration—time curve was decreased 54% and 46% by infection in the subcutaneous and oral groups, respectively. There was also a major decrease in the mean residence time in parasitized lambs. In parallel, the clearance of the drug was increased by infection. Thus, parasite infection dramatically influences the disposition of moxidectin in lambs. These results may contribute to determining a therapeutic strategy adapted to heavily infested animals.
Tissue residue depletion of moxidectin in lambs (Ovis aries) following subcutaneous administration
Food additives & contaminants. Part A, Chemistry, analysis, control, exposure & risk assessment, 2018
To date, a tissue depletion study of moxidectin (MOX) in lambs is not available. Thus, considering that lamb meat is of great commercial interest in the world, the aim of the present study was to determine the residue levels of MOX in lamb target-tissues (muscle, liver, kidney, and fat) and subsequently calculate the MOX withdrawal period. For this purpose, the target-tissues were analysed by ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Method validation was performed based on Commission Decision 2002/657/EC and VICH GL49. To quantify the analyte, matrix-matched analytical curves were constructed with spiked blank tissues. The limits of detection and quantitation were 1.5 ng g and 5 ng g, respectively for all matrices. The linearity, decision limit, detection capability accuracy, and inter- and intra-day precision of the method are reported. The lambs were treated with a single subcutaneous (s.c.) dose of 0.2 mg MOX kg body weight (bw), and we...
Moxidectin residues in lamb tissues: Development and validation of analytical method by UHPLC-MS/MS
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences, 2018
The development and validation of a throughput method for the quantitation of moxidectin residues in lamb target tissues (muscle, kidney, liver and fat) was conducted using ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). To achieve higher recovery of the analyte from the matrices, a modified QuEChERS method was used for sample preparation. The chromatographic separation was achieved using a Zorbax Eclipse Plus C18 RRHD column with a mobile phase comprising 5mM ammonium formate solution +0.1% formic acid (A) and acetonitrile +0.1% formic acid (B) in a linear gradient program. Method validation was performed based on the Commission Decision 2002/657/EC and VICH GL49. To quantify the analyte, matrix-matched analytical curves were constructed with spiked blank tissues, with a limit of quantitation of 5ngg-1 and limit of detection of 1.5ngg-1 for all matrices. The linearity, decision limit, detection capability accuracy, and inter- and intra-day repea...
Journal of Veterinary Pharmacology and Therapeutics, 2007
Estimation of absolute oral bioavailability of moxidectin in dogs using a semisimultaneous method: influence of lipid co-administration. J. vet. Pharmacol. Therap. 30, 375-380. Moxidectin is a long-acting anthelmintic drug for which little is known about its kinetic behaviour in dogs and its oral absolute bioavailability has never been reported. We studied the pharmacokinetics of moxidectin in dogs, with a special emphasis on oral bioavailability and the influence of lipid co-administration, by using a semi-simultaneous method of administration. Ten Beagle dogs were dosed orally and then intravenously (i.v.) with 0.2 mg/kg moxidectin. The oral application was conducted with or without corn oil co-administration. Moxidectin concentration-time profiles in plasma were analysed using a compartmental modelling approach, designed to fit the oral and i.v. kinetic disposition curves simultaneously. In contrast to what happens in other species, our study indicates that the bioavailability of orally given moxidectin in dogs is nearly total (90.2 ± 7.4%), and is not enhanced by lipid co-administration. The clearance, the volume of distribution, the mean residence time and the terminal half-life were similar to what was already described for other species. Finally our trial suggests that the body condition (degree of obesity) is likely to be a major determinant of moxidectin kinetics in dogs because of its modulation of the volume of distribution that indirectly controls the terminal half-life of the drug.
Influence of verapamil on the efflux and metabolism of 14C moxidectin in cultured rat hepatocytes
Journal of Veterinary Pharmacology and Therapeutics, 2001
of verapamil on the ef¯ux and metabolism of 14 C moxidectin in cultured rat hepatocytes J. vet. Pharmacol. Therap. 24, 171±177. 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 modi®cation of the bioavailability of endectocides, we studied the in¯uence of verapamil (a multidrug-resistance reversing agent) on the metabolism of 14 C moxidectin in cultured rat hepatocytes over 72 h. The metabolism of MOX remained low: 10.79 1.99% of the total 14 C 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 C 29 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 signi®cant 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.
Biopharmaceutics & Drug Disposition, 2007
This study compares plasma disposition kinetics of ivermectin and moxidectin after oral administration to beagle dogs experimentally infected with the filarial parasite, Brugia pahangi. Sixteen dogs were selected and randomly allocated into two groups of eight dogs each. Animals in each group received either ivermectin or moxidectin by oral route at a dose of 250 mg/kg. Blood samples were collected from 0.5 h up to 56 days post-treatment and the plasma was analysed by high performance liquid chromatography (HPLC). The obtained data were analysed by compartmental and non-compartmental pharmacokinetic techniques. Peak plasma concentrations (C max ) of 234.0 AE 64.3 ng/ml (mean AE SD) were obtained for moxidectin and 132.6 AE 43.0 ng/ml for ivermectin. The terminal elimination half-life was significantly (p50.01) longer in the moxidectin treated group (621.3 AE 149.3 h) than for ivermectin treated group (80.3 AE 29.8 h). A significantly (p 5 0.01) larger V ss /F was obtained for moxidectin (19.21 AE 3.61 l/kg) compared with ivermectin (5.35 AE 1.29 l/kg). The mean estimates of CL/F of moxidectin and ivermectin were 0.0220 AE 0.00381 and 0.0498 AE 0.0179 l/h/kg, respectively. The comparative plasma disposition kinetics of ivermectin and moxidectin in dogs is reported for the first time.