Pharmacokinetics and bioavailability of tolfenamic acid in sheep

Abstract

AbstractThe pharmacokinetics, bioavailability, and tolerability of tolfenamic acid (TA) were determined after treating sheep withTAvia 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 receivedTAby intravenous (IV), intramuscular (IM), subcutaneous (SC), or oral (OR) routes at 2 mg/kg. In the second group (n = 8),TAwas 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 ofTA. FollowingIM,SC, andORadministrations,TAdemonstrated different peak concentrations (Cmax) and time to reachCmax(Tmax), with a bioavailability of 163%, 127%, and 107%, respectively. The dose‐normalizedAUC0−∞revealed a significant difference among the dose groups; however, the relationship between dose andAUC0−∞was linear. Botht1/2ʎzandMRTincreased 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 followingIM,SC, andORadministrations at 2 mg/kg.TAexhibited linear kinetics and was well tolerated by the animals, except at 16 mg/kg. Thus,TAmay be used in different routes and doses (≤8 mg/kg) in sheep; however, further studies are needed to determine the clinical efficacy ofTAduring the inflammatory and painful conditions and the pharmacokinetics and safety of repeated administration in sheep.