Pharmacokinetic Studies with Trimethoprim and Different Doses of Sulfadiazine in Healthy Human Subjects

Concentrations of sulfadiazine were compared with those of sulfamethoxazole after combination treatment of sulfonamide plus trimethoprim. Sulfadiazine was used in doses of 1.6, 1.0 or 0.6 g ini, and thereafter half of the initial dose twice daily. The initial dose of sulfamethoxazole was 1.6 g and the subsequent doses 0.8 g twice daily. All of these preparations contained the same amount of trimethoprim, 320 mg initially and then 160 mg twice daily. In plasma the free minimum concentrations of sulfadiazine were more than 10 mg/l even after the lowest dose, and both after the initial dose and after subsequent doses. Because of the more favorable MIC of sulfadiazine, these are more effective free concentrations than those obtained after conventional doses of sulfisoxazole. The free minimum concentrations of sulfamethoxazole were over 15 mg/l, which were approximately the same as those after the highest dose of sulfadiazine. In urine the free effective concentrations after sulfamethoxazole and even the lowest dose of sulfadiazine were well over 100 mg/l. The apparent half-lives of sulfamethoxazole and sulfadiazine were 13.4 ± 2.8 h and 14.9 ± 8.7 h, respectively. The minimum concentrations of trimethroprim were higher than 1 mg/l on an average. There were no differences between different combinations in this respect. It is concluded that on the pharmacokinetic basis, sulfadiazine appears to be as good a choice for combinations with trimethoprim as is sulfamethoxazole. Theoretically, it is effective at the same dosage level as sulfamethoxazole. This is due to its favorable pharmacokinetic properties, namely low protein-binding and relatively low degree of metabolism. As compared with sulfisoxazole, both of these sulfonamides are overdosed, and clinical trials by using a lower dosage appear feasible.