Pharmacokinetic investigations of the combination sulfamethoxazole (SMZ) + trimethoprim (TMP) in adult humans are reported. The subjects received a single oral dose of 800 mg SMZ + 160 mg TMP in the form of 2 tablets Bactrim or 800 mg SMZ + trimethoprim+ 160 mg ¹⁴C-labelled TMP in powder form in gelatine capsules. To investigate the distribution of the drug compo-nents in the body, auxiliary experiments were conducted with rats, using 2––¹⁴C-TMP or ³⁵S-SMZ. The results may be summarized as follows: In the blood plasma of 4 persons given 2 tablets Bactrim peak concentrations of 41.4 to 62.5 μg of non-conjugated SMZ/ml were reached 2 to 4 h after medication and peak levels of 1.27 to 1.86 μg of non-metabolized TMP/ml after 1½ to 4h. The half-life of elimination from plasma, determined in the interval between the 4th and the 24th h after administration, was found to vary for non-metabolized TMP from 4.8 to 11.3 h with a mean of 8.6 h in 10 patients, and for non-acetylated, non-conjugated SMZ from 7.7 to 10.6 h with a mean of 9.0 h in 7 of the mentioned subjects. The fictive volume of distribution varied in four subjects for non-metabolized TMP from 69.0 to 133.3 litres and for non-acetylated non-conjugated SMZ from 10.2 to 16.0 litres. The concentration ratio in the plasma of the non-protein-bound, non-metabolized SMZ, i.e. its therapeutically active part, to that of TMP varied during the first 10 h following medication between 10.4 and 49.2. With regard to the mutual potentiation of the two drugs, these values lie within the optimal range, as has been established for a large spectrum of bacterial species in experiments conducted in vitro and in vivo. The concentrations of the non-acetylated non-conjugated SMZ and of the non-metabolized TMP, i. e. the bacteriostatic fractions of the drugs, in the urine of the first 12 hours after medication were found to vary in 4 healthy adults between 63 and 125 μg/ml and 58 and 158 μg/ml respectively. The corresponding values for the urine of the second 12-hour-period were 27 to 63 μg/ml for SMZ and 19 to 84 μg/mol for TMP. These concentrations ensure good antibacterial effect, the decrease in their ratio (as compared to plasma) being counteracted by the higher content of both drugs in the urine. The average cumulative urinary excretion of total SMZ found in 7 healthy adults and of total TMP determined in 3 persons reached, 12 h after medication (i. e. at the end of the normal dosage interval), 39.6 and 35.9 % of the dose respectively. The corresponding figures after 24 h were 69.2 and 58.6 %, those after 96 h 97.5 and 81.3 % of the dose.

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The passage of sulfamethoxazole (SMZ) and trimethoprim (TMP) into the human bile was examined in 10 female patients, who were carriers of a T drain introduced 2–12 days before on the occasion of cholecystectomy. Four of the subjects received a single oral dose of 800 mg SMZ + 160 mg TMP in the form of 2 tablets of Bactrim Roche, three ingested 3 and the remaining three 10 such doses at 12-hour intervals. The concentrations of the drugs in samples of plasma and bile collected at corresponding graded times after medication were then determined. The pharmacokinetic characteristics of the resulting plasma levels lie with few deviations in the normal ranges observed in healthy adults. The content of active SMZ and TMP in the bile is of an order providing very favourable conditions for a curative effect of the combination in cases of biliary infections caused by bacteria sensitive to the two drugs.