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.

[1]  R D Brown,et al.  ESTRIP, a BASIC computer program for obtaining initial polyexponential parameter estimates. , 1978, Journal of pharmaceutical sciences.

[2]  H. Mishima,et al.  Milbemycins, a new family of macrolide antibiotics: fermentation, isolation and physico-chemical properties. , 1980, The Journal of antibiotics.

[3]  D. Perrier,et al.  Noncompartmental determination of the steady-state volume of distribution for any mode of administration. , 1982, Journal of pharmaceutical sciences.

[4]  A. Y. Lu,et al.  The metabolism of avermectins B1a, H2B1a, and H2B1b by liver microsomes. , 1982, Drug metabolism and disposition: the biological fate of chemicals.

[5]  D. G. Pope,et al.  Pharmacokinetics of ivermectin administered intravenously to cattle. , 1985, Journal of pharmaceutical sciences.

[6]  E. Lacey,et al.  Pharmacokinetics of ivermectin in sheep following intravenous, intra-abomasal or intraruminal administration. , 1985, Journal of Veterinary Pharmacology and Therapeutics.

[7]  R. Shumaker.  PKCALC: a BASIC interactive computer program for statistical and pharmacokinetic analysis of data. , 1986, Drug metabolism reviews.

[8]  A. Y. Lu,et al.  Comparative in vivo and in vitro metabolism of ivermectin in steers, sheep, swine, and rat. , 1987, Drug metabolism reviews.

[9]  P. Galtier,et al.  Kinetic and insecticidal properties of ivermectin residues in the milk of dairy cows. , 1988, Journal of veterinary pharmacology and therapeutics.

[10]  Q. Mckellar,et al.  The pharmacodynamics of ivermectin in sheep and cattle. , 1988, Journal of veterinary pharmacology and therapeutics.

[11]  H. Jackson.  Ivermectin as a systemic insecticide. , 1989, Parasitology today.

[12]  A. Porras,et al.  Pharmacokinetics of Ivermectin in Animals and Humans , 1989 .

[13]  J. Pivnichny,et al.  Liquid chromatographic determination of ivermectin in animal plasma with trifluoroacetic anhydride and N-methylimidazole as the derivatization reagent. , 1990, Journal of pharmaceutical and biomedical analysis.

[14]  T. A. Jacob,et al.  Absorption, tissue distribution, and excretion of tritium-labeled ivermectin in cattle, sheep, and rat , 1990 .

[15]  J. Sutra,et al.  Ivermectin in goat plasma and milk after subcutaneous injection. , 1993, Veterinary research.

[16]  J. Steel.  Pharmacokinetics and metabolism of avermectins in livestock. , 1993, Veterinary parasitology.

[17]  C. Lanusse,et al.  Relationship between pharmacological properties and clinical efficacy of ruminant anthelmintics. , 1993, Veterinary parasitology.

[18]  Effect of formulation on the pharmacokinetics and efficacy of doramectin. , 1993, Veterinary parasitology.

[19]  K. Gration,et al.  Doramectin--a potent novel endectocide. , 1993, Veterinary parasitology.

[20]  J. D. Baggot,et al.  The absorption, distribution and elimination of anthelmintic drugs: the role of pharmacokinetics. , 1994, Journal of veterinary pharmacology and therapeutics.

[21]  J. Zulalian,et al.  Absorption, tissue distribution, metabolism, and excretion of moxidectin in cattle , 1994 .

[22]  J. Miller,et al.  Moxidectin: pharmacokinetics and activity against horn flies (Diptera: Muscidae) and trichostrongyle nematode egg production. , 1994, Veterinary parasitology.

[23]  M. Fisher,et al.  Structure and activity of avermectins and milbemycins in animal health. , 1995, Veterinary parasitology.

[24]  R. Jones,et al.  Pharmacokinetics and bioequivalence of parenterally administered doramectin in cattle. , 1995, Journal of veterinary pharmacology and therapeutics.

[25]  D. Cully,et al.  The mechanism of action of avermectins in Caenorhabditis elegans: correlation between activation of glutamate-sensitive chloride current, membrane binding, and biological activity. , 1995, The Journal of parasitology.

[26]  J. Sutra,et al.  Plasma profile study of moxidectin in a cow and its suckling calf. , 1996, Veterinary research.

[27]  P. Toutain,et al.  Comparative pharmacokinetics of doramectin and ivermectin in cattle. , 1997, Veterinary parasitology.