Pharmacokinetics and regional skin distribution of topically administered chlorpyrifos in cattle

Chlorpyrifos (CPF) is currently being repurposed for the control of cattle mange and ticks in South American countries, particularly Argentina. This study aimed to characterize the plasma availability and regional skin distribution of CPF following topical administration in healthy, non-parasitized cattle. Additionally, the effects of CPF (in vitro and in vivo) and CPF-oxon (in vitro) on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities were evaluated using blood collected from untreated and treated cattle. CPF was administered (7.5 mg/kg) along the backline of 6 heifers (days 0 and 11 post-first dose). Plasma and skin samples were collected up to 21 days post-administration. Drug concentrations in plasma and skin (retro-auricular, backline, and croup regions) were measured by HPLC. In vitro, blood AChE and BChE activities were less susceptible to CPF, with IC50 values exceeding 1000 μM. Conversely, CPF-ox showed significantly greater inhibitory potency, particularly toward erythrocyte AChE, where its IC50 was 76 % lower (p < 0.05) than for plasma AChE and 93 % lower than for BChE. No significant changes in cholinesterase activities were observed in vivo after CPF topical treatment. CPF plasma concentrations ranged from 0.06 ± 0.03 μg/mL at 6 h post-treatment (day 0.25) to 0.15 ± 0.12 μg/mL on day 21, with an AUC of 1.92 ± 0.34 μg.d/mL and a Cmax of 0.18 ± 0.11 μg/mL. The mean skin-to-plasma AUC ratios were 285, 675, and 2054 for the retro-auricular, croup, and backline regions, respectively. The acaricide's AUC was significantly higher in the backline (6.5-fold, p < 0.05) and croup (2.2-fold, p < 0.05) compared to the retro-auricular zone. The oxon metabolite was not detected in plasma or in skin. CPF pour-on demonstrated low systemic exposure, no significant cholinesterase inhibition in vivo, and uneven skin distribution in non-parasitized cattle. Given that this study was conducted in healthy cattle, a primary limitation is the lack of data on ectoparasite-induced lesion effects. Furthermore, future research must utilize more sensitive analytical techniques and extended sampling to fully characterize the systemic and skin disposition of CPF and its related metabolites.