Corum O.Corum D.D.Er A.Yildiz R.Uney K.2023-04-122023-04-122018-12-0101407783https://hdl.handle.net/20.500.12597/5219The pharmacokinetics, bioavailability, and tolerability of tolfenamic acid (TA) were determined after treating sheep with TA via different routes and doses. This crossover study was carried out with a washout period of 15 days. In the study, 16 clinically healthy sheep were randomly assigned to two equal groups. In the first group (n = 8), animals received TA by intravenous (IV), intramuscular (IM), subcutaneous (SC), or oral (OR) routes at 2 mg/kg. In the second group (n = 8), TA was administered intravenously to each sheep at 2, 4, 8, and 16 mg/kg. Plasma samples were analyzed with a high-performance liquid chromatography assay. Noncompartmental pharmacokinetic analyses were used to evaluate the data. The area under the concentration–time curves (AUC0−∞), elimination half-life (t1/2ʎz), and the mean residence time (MRT) significantly differed among the administration routes at 2 mg/kg of TA. Following IM, SC, and OR administrations, TA demonstrated different peak concentrations (Cmax) and time to reach Cmax (Tmax), with a bioavailability of 163%, 127%, and 107%, respectively. The dose-normalized AUC0−∞ revealed a significant difference among the dose groups; however, the relationship between dose and AUC0−∞ was linear. Both t1/2ʎz and MRT increased depending on the dose. Although the total clearance (ClT) decreased depending on dose, the volume of distribution at steady-state (Vss) increased. Tolfenamic acid indicated a long half-life and high bioavailability following IM, SC, and OR administrations at 2 mg/kg. TA exhibited linear kinetics and was well tolerated by the animals, except at 16 mg/kg. Thus, TA may be used in different routes and doses (≤8 mg/kg) in sheep; however, further studies are needed to determine the clinical efficacy of TA during the inflammatory and painful conditions and the pharmacokinetics and safety of repeated administration in sheep.falsebioavailability | pharmacokinetics | sheep | tolerability | tolfenamic acidArticle10.1111/jvp.127022-s2.0-8505251028530084126