Pharmacokinetics of sulphadoxine and trimethoprim and tissue irritation caused by two sulphadoxine-trimethoprim containing products after subcutaneous administration in pre-ruminant calves

The pharmacokinetics of sulphadoxine-trimethoprim was studied in 6 pre-rumi nant calves using two different products. Product A, which contained 200 mg sulphadoxine and 40 mg trimethoprim per mt, was administered intravenously or subcutaneously at a dosage of 25 mg sulphadoxine and 5 mg trimethoprim. kg(-1) bodyweight. Product B, containing 62.5 mg sulphadoxine and 12.5 mg t rimethoprim per mt plus lidocaine (1 mg.mL(-1)), was given subcutaneously a t the same dosage. After intravenous administration of product A the mean t ime of half-life of elimination phase (t(1/2)) for sulphadoxine was 12.9 h, steady-state volume of distribution (V-d(ss)) was 0.44 L.kg(-1) and cleara nce was 0.024 L.kg(-1).h(-1). Respective values for trimethoprim were 1.9 h , 2.0 L.kg(-1) and 0.9 L.kg(-1).h(-1). After subcutaneous administration, t he bioavailability of sulphadoxine was 96% and 98% and the time to reach a maximum concentration was 6.3 and 8.0 h for products A and B, respectively. The C-max for trimethoprim was higher for product A (0.49 mug.mL(-1)) than for product B (0.32 mug.mL(-1)) (p = 0.014). Slow absorption from the inje ction site appeared to delay the elimination of trimethoprim after subcutan eous administration when compared to that after intravenous administration: apparent elimination tin for trimethoprim after intravenous administration of product A was 1.9 h compared to 3.9 h and 3.6 h after subcutaneous admi nistration of products A and B, respectively. The difference between intrav enous and subcutaneous administrations was statistically significant (p < 0 .05). Also the mean residence time was significantly shorter (p, < 0.05) af ter intravenous administration (2.4 h) than that after subcutaneous adminis tration of product A (6.9 h) and B (7.1 h). The bioavailability of trimetho prim was lower than that of sulphadoxine: 76% and 74% for products A and B, respectively. All 6 calves showed pain after subcutaneous administration o f product A and the injection sites were warm and showed soft oedematous re actions 5-8 cm in diameter. Three of the calves also showed some pain after subcutaneous administration of product B; the local reactions were less se vere. A marked increase was seen in creatine kinase activity after subcutan eous administration of both products. Product A caused a more pronounced in crease but the difference was not statistically significant. We suggest 30 mg.kg(-1) at 24-h intervals or alternatively 15 mg.kg(-1) at 12-h intervals as the minimum dosage of sulphadaxine-trimethoprim combination for pre-rum inant calves. Extravascular routes of administration should be avoided due to marked tissue irritation at the injection site.