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Pharmacological particulars
ATCvet code: QP54AA51
Pharmacotherapeutic group: Anthelmintic
Pharmacodynamic Properties
Ivermectin is an endectocide with activity against a wide range of internal and external parasites. Ivermectin is a macrocylic lactone and acts by inhibiting nerve impulses. It binds selectively and with high affinity to glutamate-gated chloride ion channels which occur in invertebrate nerve and muscle cells. This leads to an increase in the permeability of the cell membrane to chloride ions with hyperpolarization of the nerve or muscle cell, resulting in paralysis and death of the relevant parasites. Compounds of this class may also interact with other ligand-gated chloride channels, such as those gated by the neurotransmitter gamma-aminobutyric acid (GABA). The margin of safety for compounds of this class is attributable to the fact that mammals do not have glutamate-gated chloride channels. The macrocylic lactones have a low affinity for other mammalian ligand-gated chloride channels and they do not readily cross the blood-brain barrier.
Closantel is a member of the salicylanilide class of anthelmintics. Salicylanilides are hydrogen (proton) ionophores (referred to as oxidative phosphorylase uncouplers.)
The chemical structure of salicylanilides illustrate the possession of a detachable proton. This type of molecule is lipophilic and is known to shuttle protons across membranes, in particular the inner mitochondrial membrane. Closantel acts by uncoupling oxidative phosphorylation.
Closantel is a parasiticide with flukicide activity and efficacy against certain other helminths and arthropods. Treatment with Closamectin when fluke are five weeks and greater has been shown to reduce subsequent reproductive capacity and egg shedding.
Pharmacokinetic Properties
Cattle:
After subcutaneous administration of Closamectin Injection to cattle at a dose rate of 200ug ivermectin per kg and 5mg closantel per kg the following parameters were observed: Ivermectin Cmax of 57.3ng/ml and AUC of 7106ng.hr/ml; Closantel Cmax of 63.4ug/ml and AUC of 21996ug.hr/ml. Ivermectin is only partially metabolised. In cattle, only about 1-2% is excreted in the urine the remainder is excreted in the faeces, approximately 60% of which is excreted as unaltered drug. The remainder is excreted as metabolites or degradation products. Salicylanilides are poorly metabolised and are excreted mainly unchanged. About 90% of closantel is excreted unchanged in the faeces and urine in cattle.
Sheep:
After subcutaneous administration of Closamectin Injection to sheep at a dose rate of 200μg ivermectin per kg and 5mg closantel per kg the following parameters were observed: Ivermectin Cmax of 24.52ng/ml and AUC of 2082.93ng.h/ml;
Closantel Cmax of 70.4μg/ml and AUC of 41043μg.h/ml.
Ivermectin binds extensively to plasma proteins. Due to its high lipophilic nature, ivermectin is extensively distributed. It tends to accumulate in fat tissue, which acts as a drug reservoir and the highest levels of ivermectin are found in liver and fat. Ivermectin is only partially metabolised. Ivermectin is mainly eliminated in the faeces as unaltered drug and faecal excretion accounts for 90% of the dose administered with <2% of the dose excreted in urine. Ivermectin is also excreted by the mammary gland.
Salicylanilides are poorly metabolised and are excreted mainly unchanged. The main excretion route is the faeces via the bile. Closantel is extensively bound to plasma proteins, almost exclusively to albumin. The distribution to tissues is poor. Closantel has a long elimination half life.