title: Loperamide-induced enhancement of moxidectin availability in cattle.
abstract: Moxidectin (MXD) is a milbemycin endectocide compound active at extremely low dosages against a wide variety of nematode and arthropod parasites. Different pharmacological approaches are currently being tested to delay the bile-faecal elimination and to obtain increased systemic availability for endectocide molecules in ruminants. Loperamide (LPM) is an opioid derivative, whose main pharmacological action is to abolish intestinal propulsive peristaltic waves. The influence of LPM on the pattern of faecal excretion of MXD and on its plasma disposition following intravenous (i.v.) and subcutaneous (s.c.) administrations to cattle was evaluated in the current work. Parasite-free calves were treated with MXD given either alone at 200 microg/kg by i.v. (Experiment 1) and s.c. (Experiment 2) administrations or coadministered with LPM subcutaneously injected at 0.4 mg/kg. Blood and faecal samples were collected over a period of 20 (Experiment 1) and 40 (Experiment 2) days post-treatment. The recovered plasma and faecal samples were extracted and analysed by high-performance liquid chromatography (HPLC) using fluorescence detection. Significantly higher MXD plasma concentrations were obtained after the coadministration of MXD + LPM compared with treatments with MXD alone by both routes. The higher MXD plasma concentration profiles measured after the coadministration with LPM accounted for the significantly higher AUC values obtained following the i.v. (> 46%) and s.c. (> 38%) treatments. A reduced MXD body clearance was observed in the presence of LPM. The appearance of MXD in faeces was significantly delayed after the i.v. and s.c. coadministrations of MXD with LPM (T(1/2app)=5.87 and 10.6 h, respectively) than that observed after the treatment with MXD alone (T(1/2app)=3.48 and 5.12 h). A delayed MXD peak concentration in faeces collected from MXD + LPM-treated animals compared with those receiving MXD alone, was observed. The delayed intestinal transit time caused by LPM and a potential competition between MXD and LPM for the P-glycoprotein-mediated bile/intestinal secretion processes, may account for the enhanced MXD systemic availability measured in cattle in the current work.
authors: Laboratorio de Farmacología, Departamento de Fisiopatología, Facultad de Ciencias Veterinarias, Universidad Nacional del Centro, Tandil, Argentina.
authors: A
authors: A
authors: Lifschitz
authors: G
authors: G
authors: Virkel
authors: J
authors: J
authors: Sallovitz
authors: F
authors: F
authors: Imperiale
authors: A
authors: A
authors: Pis
authors: C
authors: C
authors: Lanusse
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000930:Antidiarrheals / Q000008:administration & dosage / Q000494:pharmacology*; D000969:Antinematodal Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D001682:Biological Availability; D002417:Cattle / Q000378:metabolism*; D002418:Cattle Diseases / Q000188:drug therapy; D002851:Chromatography, High Pressure Liquid / Q000662:veterinary; D004357:Drug Synergism; D005243:Feces / Q000737:chemistry; D007262:Infusions, Intravenous / Q000662:veterinary; D007279:Injections, Subcutaneous / Q000662:veterinary; D008139:Loperamide / Q000008:administration & dosage / Q000494:pharmacology*; D018942:Macrolides; D008297:Male; D009349:Nematode Infections / Q000188:drug therapy / Q000662:veterinary
chemical_list: D000900:Anti-Bacterial Agents; D000930:Antidiarrheals; D000969:Antinematodal Agents; D018942:Macrolides; D008139:Loperamide; C027837:moxidectin