Introduction Sulphonamides are some of the most widely used antimicrobial drugs in the treatment of bacterial diseases in pigs. The study was conducted to compare the total exposure of tissue to a group of active substances in a single formulation and evaluate the impact of the volume of distribution, lipophilicity and tissue half-life of sulfadimethoxine, sulphathiazole, sulphamethazine and sulphacetamide in two different veterinary drug formulations – Polisulfalent, which was preparation A, and Polisulfamid, which was preparation B. Material and Methods Each tested therapeutic preparation was administered to 15 piglets of the Polish Landrace breed. To assume general exposure expressed as the sum of all observed concentrations of all active substances, semi-log regression analyses were performed for both formulations. Results The estimated tissue half-life was 21.19 h for preparation A and 17.36 h for preparation B. The comparison of the semi-log regression parameters shows that formulation B’s Y-intercept and slope values were higher than formulation A’s. The upper-bound CI for the Y-intercept and slope value of formulation B was higher than those of formulation A, at 38.7 and 20.8%, respectively. The lower-bound CI for the Y-intercept and slope value of formulation B was also higher than those of formulation A, at 20.6 and 42.9%, respectively. Conclusion Current observations lead to the conclusion that in late-stage drug elimination, it is not the blood half-life, but rather a drug’s volume of distribution which is key in determining the clearance period, this volume being dependent on the physicochemical characteristics of the drug.