Pharmacokinetics of metaflumizone and amitraz in the plasma and hair of dogs following topical application.

Controlled laboratory studies have shown that a metaflumizone plus amitraz combination (ProMeris/ProMeris Duo for Dogs, Fort Dodge Animal Health, Overland Park, KS) applied topically is effective for the treatment and control of fleas and ticks on dogs. Two studies were conducted to determine the distribution of both metaflumizone and amitraz in the plasma and hair of dogs following treatment at the minimum recommended dose of approximately 20mg/kg of each active ingredient. Six purpose-bred, adult Beagle dogs were used in each study. Plasma or hair samples were collected from each dog just prior to dosing and periodically through 56 days after treatment. Samples were analyzed by HPLC methods validated for the simultaneous determination of metaflumizone and amitraz. Amitraz was detectable (>3.2ng/ml) but not quantifiable (<50ng/ml) in only two plasma samples, collected 1 and 2 days post-treatment from different dogs. Metaflumizone concentrations in plasma were generally detectable (>1.0ng/ml) but not quantifiable (<50ng/ml). Measurable levels were found in one dog 7 days post-treatment, increasing to a maximum of four dogs at 42 days after dosing, with a metaflumizone range of 59-138ng/ml. Analysis of hair samples indicated that both metaflumizone and amitraz were widely distributed at basically similar levels in the hair within 1-day after administration, reaching maximum concentrations between 2 and 7 days post-treatment. Low but quantifiable levels of both compounds were still present on hair at the end of the 56-day study. These studies indicate that the ectoparasitic activity is due to exposure of the parasites to metaflumizone and amitraz on the surface of the host (hair and/or skin), not to exposure via the circulatory system of the host.

Pharmacokinetics of metaflumizone in the plasma and hair of cats following topical application.

Controlled laboratory studies have shown that a novel spot-on formulation containing 20% (w/v) metaflumizone (ProMeris for Cats, Fort Dodge Animal Health, Overland Park, KS) is effective for the treatment and control of fleas on cats. Two studies were conducted to determine the distribution of metaflumizone in the plasma and hair of cats following treatment at the minimum recommended dose of 40mg/kg. Six purpose-bred cats, three males and three females, were used in each study. Plasma or hair samples were collected from each cat just prior to dosing and periodically through 56 days after treatment. Samples were analyzed by HPLC methods validated for the determination of metaflumizone. Metaflumizone concentrations in plasma were below the method limit of quantification (<50ng/ml) in all samples but one, and were frequently not detectable (<1.1ng/ml). Plasma collected 3 days post-treatment from one cat had a metaflumizone concentration of 57.8ng/ml. The frequency of measurable levels of metaflumizone in the plasma was too low to allow the calculation of pharmacokinetic parameters. Analysis of hair samples indicated that metaflumizone was widely distributed in the hair coat of the cat within 1 day after administration, reaching maximum concentrations within 1 or 2 days post-treatment. Low but quantifiable levels were still present at the end of the 56-day study. Data from the present studies indicate that the ectoparasitic activity is due to exposure of the parasites to metaflumizone on the surface of the host (skin and hair), not to exposure via the circulatory system of the host.

Development of a high-performance liquid chromatographic-tandem mass spectrometric method for the determination of pharmacokinetics of Co 102862 in mouse, rat, monkey and dog plasma.

A method for determining concentration levels of Co 102862 in mouse, rat, monkey and dog plasma was validated in the range of 5 to 2000 ng/ml using 200 microl plasma sample volume. This validation report describes the linearity, specificity, sensitivity, reproducibility, accuracy, recovery and stability of the analytical method. The inter-day RSD ranged from 3.5 to 10.1%, intra-day RSD from 0.6 to 5.7% and intra-day accuracy (mean absolute percent difference) ranged from 2.2 to 14.9% for rat, monkey and dog plasma. A mini-validation (5-2000 ng/ml) of Co 102862 was performed in mouse plasma using the same methods. Additionally, the assay range at the low end was successfully extended to 0.5 ng/ml for monkey plasma. The method was used for the routine analysis of Co 102862 in mouse, rat, monkey and dog plasma and summary of the pharmacokinetic data are presented.

In vivo metabolism and mass balance of 4-[4-fluorophenoxy]benzaldehyde semicarbazone in rats.

The pharmacokinetics, mass balance, tissue distribution, and metabolism of Co 102862 was investigated in rats after a single oral dose. [(14)C]Co 102862 showed multiexponential pharmacokinetics in rat plasma with an extensive distribution phase. After p.o. administration (approximately 10 mg/kg), the half-lives were long for total radioactivity compared with unchanged Co 102862. Profiles of rat urine and bile suggest that Co 102862 is extensively metabolized in vivo. [(14)C]Co 102862 was extensively distributed into all tissues, with the fatty tissues and secretory glands tissues containing the highest radioactivity. Elimination of radioactivity from the tissues had an estimated half-life of 14 days. A total of 91% of the administered radioactivity was recovered in both intact and bile-duct cannulated rats over 120 and 48 h, respectively, with the majority ( approximately 74%) of the radioactivity being excreted in the urine. Approximately 10% of the total radioactivity remained in the tissues on day 5 and decreased with time to approximately 3% on day 28. Bile-duct cannulated experiments show the enterohepatic circulation is an important route of elimination and reabsorption. Six metabolites were identified in the urine and bile of which the carboxylic acid was the major metabolite. The carboxylic acid was the only metabolite found in plasma and was probably responsible for the radioactivity in the tissues.

[Quantitative determination of drugs by in situ spectrophotometry of chromatograms for pharmacokinetic studies. I. Sulpiride and other benzamides, vincamine, naftazone (author's transl)]. / Dosage des médicaments par spectrophotométrie in situ des chromatogrammes en vue de leur étude pharmacocinétique. I. Sulpiride et autres benzamides, vincamine, naftazone.

Assays are proposed for sulpiride and other benzamides, vincamine and naftazone in plasma (or blood) and urine with direct UV reflectance spectrophotometry on this are applied directly on TLC along with a calibration curve on each plate. Plasma (or total blood) samples are extracted, and an internal standard is added before aplication; slopes of the obtained calibration curves do not change significantly from plate to plate, thus allowing several determinations on the same plate. The sensitivity is 2 microgram in a 1-ml sample (amount applied 30 ng) for sulpiride and related compounds and about the same for vincamine. Naftazone is determined in plasma with simultaneous reflectance and transmittance spectrophotometric measurements at 520 nm on chromatoplates sprayed with lead acetate, the sensitivity reached is 10 ng in a 1-ml sample (amount applied 0.5 ng). For all drugs studied, the proposed techniques are specific, reliable and sensitive enough and can be used to perform pharmacokinetic studies in human or in animal after administration of doses in the therapeutic range.