Mechanism of Action: Aminosalicylic acid is bacteriostatic against Mycobacterium tuberculosis. It inhibits the onset of bacterial resistance to streptomycin and isoniazid. The mechanism of action has been postulated to be inhibition of folic acid synthesis (but without potentiation with antifolic compounds) and/or inhibition of synthesis of the cell wall component, mycobactin, thus reducing iron uptake by M. tuberculosis.
Characteristics: The two major considerations in the clinical pharmacology of aminosalicylic acid are the prompt production of a toxic inactive metabolite under acid conditions and the short serum half life of one hour for the free drug. Both are discussed below.
After two hours in simulated gastric fluid, 10% of unprotected aminosalicylic acid is decarboxylated to form meta-aminophenol, a known hepatotoxin. The acid-resistant coating of the PASER granules protects against degradation in the stomach. The small granules are designed to escape the usual restriction on gastric emptying of large particles. Under neutral conditions such as are found in the small intestine or in neutral foods, the acid-resistant coating is dissolved within one minute. Care must be taken in the administration of these granules to protect the acid-resistant coating by maintaining the granules in an acidic food during dosage administration. Patients who have neutralized gastric acid with antacids will not need to protect the acid resistant coating with an acidic food since no acid is present to spoil the drug. Antacids may influence the absorption of other medications and are not necessary for PASER consumed with an acidic food.
Because PASER granules are protected by an enteric coating absorption does not commence until they leave the stomach; the soft skeletons of the granules remain and may be seen in the stool.
Absorption and excretion: In a single 4 gram pharmacokinetic study with food in normal volunteers the initial time to a 2μg/mL serum level of aminosalicylic acid was 2 hours with a range of 45 minutes to 24 hours; the median time to peak was 6 hours with a range of 1.5 to 24 hours; the mean peak level was 20 μg/mL with a range of 9 to 35 μg/mL; a level of 2 μg/mL was maintained for an average of 7.9 hours with a range of 5 to 9; a level of 1 μg/mL was maintained for an average of 8.8 hours with a range of 6 to 11.5 hours. The recommended schedule is 4 grams every 8 hours.
80% of aminosalicylic acid is excreted in the urine, with 50% or more of the dosage excreted in acetylated form. The acetylation process is not genetically determined as is the case for isoniazid. Aminosalicylic acid is excreted by glomerular filtration; although previously reported otherwise, probenecid, a tubular blocking agent, does not enhance plasma concentration. In a 1954 study thyroxine synthesis but not iodide uptake was reported reduced about 40% when the sodium salt (not PASER granules) of aminosalicylic acid was administered one hour before radio-iodine; the sodium salt typically produces a serum level over 120 μg/mL at one hour lasting one hour. Occasional goiter development can be prevented by the administration of thyroxine but not iodide.
Penetration into the cerebrospinal fluid occurs only if the meminges are inflamed.
Approximately 50-60% of aminosalicylic acid is protein bound; binding is reported to be reduced 50% in kwashiorkor.
Microbiology: The aminosalicylic acid MIC for M. tuberculosis in 7H11 agar was less than 1.0 μg/mL for nine strains including three multidrug resistant strains, but 4 and 8 μg/mL for two other multidrug resistant strains. The 90% inhibition in 7H12 broth (Bactec) showed little dose response but was interpreted as being less than or equal to 0.12-0.25 μg/mL for eight strains of which three were multi-resistant, 0.50 μg/mL for one resistant strain, questionable for four non-resistant strains and greater than 1μg/mL for one non-resistant and three resistant strains. Aminosalicylic acid is not active in vitro against M. avium.