PAS is administered orally in the form of the sodium salt, usually in tablet or capsule form. Symptoms of gastrointestinal irritation are common with both the acid and the sodium salt. Various enteric-coated dosage forms have been used in an attempt to overcome this disadvantage. Other forms that are claimed to improve gastrointestinal tolerance include the calcium salt, the phenyl ester, and a combination with an anion exchange resin (Rezi-PAS). An antacid such as aluminum hydroxide is frequently prescribed.
The oral absorption of PAS is rapid and nearly complete, and it is widely distributed into most of the body fluids and tissues, with the exception of the CSF, in which levels are significantly lower. It is excreted primarily in the urine as both unchanged drug and metabolites. The N-acetyl derivative is the principal metabolite, with significant amounts of the glycine conjugate also being formed. When administered with isoniazid (which also undergoes N-acetylation), PAS increases the level of free isoniazid. The biological half-life of PAS is about 2 hours.
The mechanism of antibacterial action of PAS is similar to that of the sulfonamides. Thus, it is believed to prevent the incorporation of p-aminobenzoic acid (PABA) into the dihydrofolic acid molecule catalyzed by the enzyme dihy-drofolate synthetase. Structure-activity studies have shown that the amino and carboxyl groups must be para to each other and free; thus, esters and amides must readily undergo hydrolysis in vivo to be effective. The hydroxyl group may be ortho or meta to the carboxyl group, but optimal activity is seen in the former.
For many years, PAS was considered a first-line drug for the chemotherapy of tuberculosis and was generally included in combination regimens with isoniazid and streptomycin. However, the introduction of the more effective and generally better tolerated agents, ethambutol and rifampin, has relegated it to alternative drug status.
Sodium 4-aminosalicylate (sodium PAS), a salt, occurs in the dihydrate form as a yellow-white powder or crystalline solid. It is very soluble in water in the pH range of 7.0 to 7.5, at which it is the most stable. Aqueous solutions decompose readily and darken. Two pH-dependent types of reactions occur: decarboxylation (more rapid at low pH) and oxidation (more rapid at high pH). Therefore, solutions should be prepared within 24 hours of administration.
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