Pharmacodynamic assessment and skin exposure of topically administered chlorpyrifos in cattle

Abstract

Chlorpyrifos (CPF) is currently being repurposed for the control of cattle mange and ticks. CPF is used topically as a pour-on formulation, or through dipping and aspersion methods. CPF and its oxon metabolite (CPF-ox) are irreversible inhibitors of acetylcholinesterases (AChEs) and butyrylcholinesterases (BChEs) in both target parasites and treated animals. This work evaluated the effects of CPF (in vitro and in vivo) and CPF-ox (in vitro) on AChE and BChE activities in cattle plasma, and the availability of CPF in cattle skin and plasma following its topical administration. CPF was administered (7.5 mg/kg) along the backline of 6 heifers on days 0 and 11 post-first dose. Plasma and skin samples were collected before the initial treatment up to 20 days post-administration. Drug concentrations in plasma and skin (retroauricular, backline, and croup regions) were measured by HPLC. The IC50s of CPF for the in vitro inhibition of AChE and BChE activities in plasma were greater than 1000 µM. CPF-ox was roughly 500 times more potent AChE inhibitor and 150 times more potent BChE inhibitor. The IC50 of CPF-ox for AChE activity (1.9±1.1 µM) was lower (p=0.037) than that for BChE activity (6.8±4.3 µM). CPF did not change plasma AChE and BChE activities in treated animals. CPF concentrations in plasma were between 0.07±0.03 µg/mL (day 0.25) to 0.16±0.11 µg/mL (day 20). Drug exposure in the skin, measured as AUC (µg/d.g), was higher (p<0.05) in the backline (2218±1872) compared to other skin areas (521±138). Notably, higher (p<0.05) CPF partial AUCs were observed following the second dose. The absence of inhibitory effects on cholinesterase activities in plasma indicates low plasma levels of CPF, underscoring its safety for treated animals. Although CPF was detected in various skin regions, its distribution was not uniform. Therefore, repeating the treatment at intervals of 8-11 days is crucial to increase skin drug exposure and enhance the efficacy against ectoparasites.