SEPTRA is rapidly absorbed following oral administration. Both sulfamethoxazole and trimethoprim exist in the blood as unbound, protein-bound, and metabolized forms; sulfamethoxazole also exists as the conjugated form. The metabolism of sulfamethoxazole occurs predominately by N₄-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 sulfamethoxazole and trimethoprim are considered to be the therapeutically active forms. Approximately 44% of trimethoprim and 70%o 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.

Peak blood levels for the individual components occur 1 to 4 hours after oral administration. The mean serum half-lives of sulfamethoxazole and trimethoprim are 10 and 8 to 10 hours, respectively. However, patients with severely impaired renal function exhibit an increase in the half-lives of both components, requiring dosage regimen adjustment (See DOSAGE AND ADMINISTRATION). Detectable amounts of trimethoprim and sulfamethoxazole are present in the blood 24 hours after drug administration. During administration of 160 mg trimethoprim and 800 mg sulfamethoxazole b.i.d., the mean steady- state plasma concentration of trimethoprim was 1.72 mcg/mL. The steady-state minimal plasma levels of free and total sulfamethoxazole were 57.4 mcg/mL and 68.0 mcg/mL, respectively. These steady- state levels were achieved after 3 days of drug administration.¹

Excretion of sulfamethoxazole and trimethoprim is primarily by the kidneys through both glomerular filtration and tubular secretion. Urine sulfamethoxazole and trimethoprim are considerably higher than are the concentrations in the blood. The average percentage of the dose recovered in urine from 0 to 72 hours after a single oral dose is 84.5% for total sulfonamide and 66.8% for free trimethoprim. Thirty percent of the total sulfonamide is excreted as free sulfamethoxazole, with the remaining as N₄-acetylated metabolite.² When administered together as SEPTRA, neither sulfamethoxazole nor trimethoprim affects the urinary excretion pattern of the other.

Both trimethoprim and sulfamethoxazole distribute to sputum, vaginal fluid, and middle ear fluid; trimethoprim also distributes to bronchial secretions, and both pass the placental barrier and are excreted in human milk.

Geriatric Pharmacokinetics

The pharmacokinetics of sulfamethoxazole 800 mg and trimethoprim 160 mg were studied in 6 geriatric subjects (mean age: 78.6 years) and 6 young healthy subjects (mean age: 29.3 years) using a non-US approved formulation. Pharmacokinetic values for sulfamethoxazole in geriatric subjects were similar to those observed in young adult subjects. The mean renal clearance of trimethoprim was significantly lower in geriatric subjects compared with young adult subjects (19 mL/h/kg vs. 55 mL/h/kg). However, after normalizing by body weight, the apparent total body clearance of trimethoprim was an average 19% lower in geriatric subjects compared with young adult subjects.³

Microbiology

Sulfamethoxazole inhibits bacterial synthesis of dihydrofohc acid by competing with para-aminobenzoic acid (PABA). Trimethoprim blocks the production of tetrahydrofolic acid from dihydrofohc acid by binding to and reversibly inhibiting the required enzyme, dihydrofolate reductase. Thus, SEPTRA 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 SEPTRA than with either trimethoprim or sulfamethoxazole alone.

In vitro serial dilution tests have shown that the spectrum of antibacterial activity of SEPTRA includes the common urinary tract pathogens with the exception of Pseudomonas aeruginosa. The following organisms are usually susceptible: Escherichia coli, Klebsiella species, Enterobacter species, Morganella morganii, Proteus mirabilis, and indole-positive Proteus species including Proteus vulgaris.

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