Pharmacokinetics of monepantel and its sulfone metabolite, monepantel sulfone, after intravenous and oral administration in sheep

Abstract

The pharmacokinetic properties of the developmental Amino-Acetonitrile Derivative (AAD), monepantel and its sulfone metabolite, monepantel sulfone were investigated in sheep following intravenous (i.v.) and oral administrations. The sulfone metabolite was rapidly formed and predominated over monepantel 4 h after dosing, irrespective of the route of administration. The steady-state volume of distribution, total body clearance and mean residence time of monepantel were 7.4 L/kg, 1.49 L/(kg x h) and 4.9 h, respectively and 31.2 L/kg, 0.28 L/(kg x h) and 111 h, respectively for monepantel sulfone. The overall bioavailability of monepantel was 31%, but it was demonstrated that approximately the same amount of monepantel sulfone was produced whether monepantel was given intravenously or orally (AUC((0-infinity)) oral/AUC((0-infinity)) i.v. of 94% for monepantel sulfone), making oral administration a very efficient route of administration for monepantel in terms of the amount of sulfone metabolite generated. Because monepantel sulfone is the main chemical entity present in sheep blood after monepantel administration and because it is also an active metabolite, its pharmacokinetic properties are of primary importance for the interpretation of future residue and efficacy studies. Overall, these pharmacokinetic data aid in the evaluation of monepantel as an oral anthelmintic in sheep.

Monepantel Allosterically Activates DEG-3/DES-2 Channels of the Gastrointestinal NematodeHaemonchus contortus

“…Here, we demonstrate that monepantel sulfone (AAD-4670), the major metabolite of monepantel in sheep (Karadzovska et al, 2009), potentiates the choline-activated currents mediated by H. contortus DEG-3/DES-2 receptors in a concentrationdependent way (Fig. 4) without opening the channels by itself.…”

“…In case the compounds reached the brain, our data indicate that the major inhibitory neurotransmitter receptor, the GABA A receptor, would remain unaffected. Because monepantel is rapidly converted to the sulfone in vivo (Karadzovska et al, 2009), the fact that 10 M monepantel slightly affected GABA A receptors is probably of little significance.…”

“…However, there has so far been no direct evidence for action of AADs on DEG-3 type AchR channels. Here we functionally express H. contortus nAChR channels of the DEG-3 subfamily in X. laevis oocytes, with particular reference to the mode of action of monepantel (AAD-1566) and its major active metabolite monepantel sulfone (AAD-4670) (Karadzovska et al, 2009). We show that the channel formed by Hco-DEG-3 and Hco-DES-2 is allosterically potentiated by monepantel and monepantel sulfone.…”

Monepantel Irreversibly Binds to and Opens Haemonchus contortus MPTL-1 and Caenorhabditis elegans ACR-20 Receptors

“…We tested the effects of monepantel sulfone (AAD-4670) on the H. contortus MPTL-1 receptor as this compound is the major metabolite of monepantel in sheep (Karadzovska et al, 2009) that forms within hours of animal treatment, and has longer half-life than monepantel. It was also interesting to test the optical R-enantiomer of monepantel (AAD-2224), which has no nematocidal effect.…”

EVOLUTION IN CHEMOTHERAPY OF HUMAN AND ANIMAL HELMINTHIASES (review)

“…The most active metabolite is monepantel sulfone (81,82); this substance is effective in low doses (2.5-3.5 mg/kg) against a broad spectrum of gastro-intestinal helminths in larval and adult stages resistant to conventional anthelmintics (83). Interaction of monepantel with nematode-specific nAChR Hco-MPTL-1 leads to dysfunction of this receptor which paralyzes helminth's muscles (84,85).…”