The bioavailability of a drug is directly dependent on the rate and degree of absorption of the drug at the site of administration. Factors that affect the absorption of the drug, including patterns for the pour-on application, will directly affect the bioavailability of the drug. Our results suggest that the drug dispersion pattern long vs short, does not represent a relevant variable when the correct dose is respected. The topical absorption of pour-on formulation can be explained through the Fick law of diffusion in which the drug molecule moves according to the concentration gradient from a higher drug concentration to a lower one until equilibrium is reached (9). Although in our study we doubled the absorption surface, we did not modify the dose, therefore the concentration was decreased per contact surface, which possibly determined that the passive diffusion of the drug was not significantly modified.
When redosing lipophilic drugs such as fluazuron at established times, not only the pharmacokinetic profile on the dam is affected, but also the plasma levels on lactating calves. After pour-on treatment at 1.5 mg/kg, the mean plasma levels remained quite stable between 9 and 35 days after treatment, ranging from 35 to 41 ppb and declined at about 7 ppb at 16 weeks (10). Using the same dose and formulation, but from a single administration and during a short period of time, Ferreira et al., (2019) reported lower plasma concentration values. In our study, the dosing interval was set at 4–6 weeks following the manufacturer recommendations and the governmental guidelines on tick control for Uruguay, which could explain the higher concentration levels of fluazuron found in cattle and calves. The Committee for Medical Products for Veterinary Use (11) issued a Summary report on fluazuron pharmacokinetic behavior, with fluazuron being excreted via cow's milk to calves, resulting in higher plasma and fat residue levels in calves compared to the ones in cows.
Accumulation is usually considered with regard to plasma, overlooking accumulation of the drug in tissues with poor blood perfusion (12), leaving the accumulation of drug concentration on lactating animals relegated when it comes to explaining whether accumulation occurs and the possible impacts of such process. According to (11), a steady state between absorption and elimination was observed for three to four weeks after treatment. When a single dose of fluazuron is administered topically to cattle, the depletion from plasma is slow, with an elimination half-life of 10.5 weeks. Therefore, multiple doses could lead to drug accumulation both in the cow and the calves. As reported by (11) multiple treatments with 12-week intervals did not lead to accumulation of fluazuron residues.
The greater accumulation of this acaricide in lactating calves in relation to cows and the increase between subsequent administrations, could be explained by the continuous intake via the digestive tract through milk. Different authors document the importance of licking in the topical administrations and the relative importance of the dermal and oral routes in the removal of drugs from the skin (13, 14). We ruled out the licking effect since at the time of application we made a quick visual inspection and determined a null licking behavior in the first hours after applying all treatments (Unpublished Data). As stated by (15), excretion of parent compounds and/or their metabolites from plasma into milk is a complex process related with physico-chemical properties and membrane interactions. Fat content is one of the main factors that contribute to the concentration of hydrophobic drugs into milk (16, 17). Given the lipophilic characteristic of fluazuron, fat and milk residue levels are expected to be higher than the plasma levels.
In this study, the prevalence and burden of R. microplus found in the animals is consistent with the data provided by the conceptual epidemiological model described by (1) for Uruguay. Under ideal conditions of temperature and relative humidity (27°C and over 80% RH), the first generation of ticks takes place between August and October while the second generation appears from December to February. The tick populations parasitizing cattle are higher in relation to the first generation, with an average of 25 ticks per animal. Considering that the study was carried out in a farm with a history of presence of ticks in previous autumn months, and that the prevalence was lower than expected by the epidemiological model, we can consider that the concentration levels of fluazuron in the animals were sufficient to prevent the development of the parasitic cycle of the tick.
The rational use of drugs is crucial in food-producing animals because of the potential adverse effects of drugs that appear as residues in edible tissues (18–20). Milk excretion needs to be quantified in order to understand the pharmacokinetic changes that could occur during the suckling period and the impact on parasites control and drug residue levels, especially on parasites with high health impact such as R. microplus. Further studies are needed to quantify milk excretion of fluazuron under pour-on administration on lactating cows. Achieving a pharmacokinetic model for this excretion route is the first step on understanding the use of this chemical tool for tick control around parturition.