Following a 1-hour intravenous infusion of a single dose of 160 mg trimethoprim and 800 mg sulfamethoxazole to 11 patients whose weight ranged from 105 lbs to 165 lbs (mean, 143 lbs), the peak plasma concentrations of trimethoprim and sulfamethoxazole were 3.4 ± 0.3 µg/mL and 46.3 ± 2.7 µg/mL, respectively. Following repeated intravenous administration of the same dose at 8-hour intervals, the mean plasma concentrations just prior to and immediately after each infusion at steady state were 5.6 ± 0.6 µg/mL and 8.8 ± 0.9 µg/mL for trimethoprim and 70.6 ± 7.3 µg/mL and 105.6 ± 10.9 µg/mL for sulfamethoxazole. The mean plasma half-life was 11.3 ± 0.7 hours for trimethoprim and 12.8 ± 1.8 hours for sulfamethoxazole. All of these 11 patients had normal renal function, and their ages ranged from 17 to 78 years (median, 60 years). ¹

Pharmacokinetic studies in children and adults suggest an age-dependent half-life of trimethoprim, as indicated in the following table. ²

Patients with severely impaired renal function exhibit an increase in the half-lives of both components, requiring dosage regimen adjustment (See DOSAGE AND ADMINISTRATION section).

Both trimethoprim and sulfamethoxazole exist in the blood as unbound, protein-bound and metabolized forms; sulfamethaxazole also exists as the conjugated form. The metabolism of sulfamethoxazole occurs predominately by N ₄ -acetylation, although the glucuronide conjugate has been identified. The principal metabolites of trimethoprim are the 1- and 3-oxides and the 3'- and 4'-hydroxy derivatives. The free forms of trimethoprim and sulfamethoxazole are considered to be the therapeutically active forms. Approximately 44% of trimethoprim and 70% of sulfamethoxazole are bound to plasma proteins. The presence of 10 mg percent sulfamethoxazole in plasma decreases the protein binding of trimethoprim by an insignificant degree; trimethoprim does not influence the protein binding of sulfamethoxazole.

Excretion of trimethoprim and sulfamethoxazole is primarily by the kidneys through both glomerular filtration and tubular secretion. Urine concentrations of both trimethoprim and sulfamethoxazole are considerably higher than are the concentrations in the blood. The percent of dose excreted in urine over a 12-hour period following the intravenous administration of the first dose of 240 mg of trimethoprim and 1200 mg of sulfamethoxazole on day 1 ranged from 17% to 42.4% as free trimethoprim; 7% to 12.7% as free sulfamethoxazole; and 36.7% to 56% as total (free plus the N ₄ -acetylated metabolite) sulfamethoxazole. When administered together as Bactrim, neither trimethoprim nor sulfamethoxazole affects the urinary excretion pattern of the other. Both trimethoprim and sulfamethoxazole distribute to sputum and vaginal fluid; trimethoprim also distributes to bronchial secretions, and both pass the placental barrier and are excreted in breast milk.

Microbiology:   Sulfamethoxazole inhibits bacterial synthesis of dihydrofolic acid by competing with para  -aminobenzoic acid (PABA). Trimethoprim blocks the production of tetrahydrofolic acid from dihydrofolic acid by binding to and reversibly inhibiting the required enzyme, dihydrofolate reductase. Thus, Bactrim blocks two consecutive steps in the biosynthesis of nucleic acids and proteins essential to many bacteria.

In vitro studies have shown that bacterial resistance develops more slowly with Bactrim than with either trimethoprim or sulfamethoxazole alone.

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