Development of sulphonamide-trimethoprim combinations for urinary tract infections

Abstract

Plasma levels and renal excretion of sulphonamide and trimethoprim following oral administration of co-trimazine (140 mg sulphadiazine + 90 mg trimethoprim) and co-trimoxazole (800 mg sulphamethoxazole + 180 mg trimethoprim) were monitored in healthy volunteers after a single dose and in the steady state after 12-hourly dosage. The plasma levels of free, non-protein bound components after co-trimazine were approximately half those after co-trimoxazole and thus correlated with the doses given. Urine recovery of trimethoprim was better after co-trimazine (70%) than after co-trimoxazole (58%). Sixty-six percent of the sulphadiazine was recovered as unchanged, active sulphonamide in the urine compared with only 13% of the sulphamethoxazole. Consequently, the sulphonamide levels of sulphadiazine were 2.5 times those of sulphamethoxazole. With respect to plasma half-life after the first dose, sulphadiazine with 8.0 hours was closer to trimethoprim with a half-life of 8.8 hours after cotrimazine and 9.6 hours after co-trimoxazole than to the half-life of sulphamethoxazole which was 7.7 hours. The distribution volume of sulphadiazine was closer to that of trimethoprim than was that of sulphamethoxazole. On the basis of these characteristics, it has been concluded that sulphadiazine is more suitable for a fixed combination tablet with trimethoprim than sulphamethoxazole, particularly for the treatment of urinary tract infections. Some renal tubular reabsorption occurs with both unchanged sulphonamides but is more pronounced with sulphamethoxazole. The solubilities of the sulphonamides and their acetylated metabolites at acid urinary pH indicate that therapy with co-trimazine is at least as safe as with co-trimoxazole. With the former drug, the result of scrutiny for crystals after dosage until the steady state was negative, whereas crystals of acetylated sulphamethoxazole were detected and verified chemically in two of eight subjects.

Pharmacokinetics of Oral Co-Trimazine and the Penetration of Its Components Sulfadiazine and Trimethoprim into Peripheral Human Lymph

“…The present serum concentrations and pharmacokinetic characteristics of the cotrimazine components are consistent with previous studies [19,20], The concentra tions reflected by both the cmax and the areas under the curves were 1.5-2.0 times higher in both serum and lymph during steady state than after the first dose. This is an expected consequence due the order of t'A of SDZ and TMP.…”

“…Serum t Vi of TMP was similar to that in previous observations [5,19,20,23,24], i.e. 8.8-10.6 h [20], Serum t'/> of SDZ was longer than previously found with one dose [19,20].…”

“…Pharmaco kinetic assessments of serum and urine data have suggested SDZ to be an optimal partner for TMP in a fixed combination product because of similar pharmacoki netic properties [12,19,20], However, it would be useful if the distribution of SDZ and TMP to extracellular tissue fluid could be studied for possible verification of this point. The protein binding and the circumstance that one of the agents is a weak acid (SDZ) while the other is a weak base (TMP) will influence passage of the agents to extravascular foci.…”

Penetration of Trimethoprim and Sulfadiazine into Sinus Secretion in Acute Maxillary Sinusitis

“…The same goes even more with other sulfonamides which have less favor able penetration properties [19]. Hence the therapeutic effect of TMP/SA in the sinu sitis is preferably caused by TMP.…”

Pharmacokinetics of Methioprim in Human Volunteers

“…The plasma half-life of methioprim is thus of the same order as that usually found for trimethoprim. Values of 8.8 and 9.6 h after the first and 10.2 and 14.0 h af ter the second have been reported in a cross-over study on healthy volunteers where the trimethoprim was given with sulphadiazine and sulphamethorazole, re spectively [5]. A recent detailed review has mentioned 1 I h as the usual ty, for methio prim [6].…”