Comparative pharmacokinetics of trimethoprim–sulfadiazine and trimethoprim–sulfamethoxazole in dogs

Background: Potentiated sulphonamides, combining trimethoprim (TMP) with a sulphonamide such as sulfadiazine (SDZ) or sulfamethoxazole (SMX), are widely used in canine medicine. The standard 1:5 dose ratio was initially designed to achieve a plasma concentration ratio of approximately 1:19 in humans, considered optimal for antibacterial synergy. However, species differences in pharmacokinetics may influence whether this ratio is achieved and maintained in dogs. Updated pharmacokinetic data based on modern analytical techniques and unbound (active) drug concentrations are lacking. This study aimed to characterise and compare the pharmacokinetics and plasma protein binding of TMP/SDZ and TMP/SMX in dogs. Methods: Beagle dogs were administered TMP/SDZ or TMP/SMX intravenously and orally in a crossover design. In addition, TMP was administered orally alone once. Plasma concentrations of TMP, SDZ and SMX were quantified using ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC–MS/MS). Population pharmacokinetic analysis was performed using nonlinear mixed-effects modelling. Protein binding was determined by ultrafiltration, and free fractions were estimated using linear mixed-effects models. Results: Oral bioavailability was high for all compounds (93–97%). TMP exhibited substantially higher clearance (0.44 L/h/kg) and a shorter elimination half-life (4.2 h) than SDZ (0.05 L/h/kg; 7.6 h) and SMX (0.026 L/h/kg; 12.6 h). TMP also showed a markedly larger apparent volume of distribution (2.67 L/kg) compared to the sulphonamides (approximately 0.5 L/kg). Protein binding differed between compounds, with population mean free fractions of 0.50 for SDZ, 0.33 for SMX, and 0.43 for TMP. Following both intravenous and oral administration, the free sulphonamide-to-TMP concentration ratios were only close to the proposed 1:19 ratio during the first hours after dosing. Thereafter, the ratios progressively increased due to the more rapid elimination of TMP. Conclusions: TMP/SDZ and TMP/SMX display distinct pharmacokinetic profiles in dogs, particularly with respect to clearance, half-life and protein binding. The commonly used 1:5 dose ratio does not maintain a stable 1:19 free concentration ratio over a 12 h dosing interval. These findings provide clinically relevant pharmacokinetic data to support rational and species-specific use of potentiated sulphonamides in dogs.