4-Aminosalicylic acid

Molecular mass: 153.135 g/mol  PubChem compound: 4649

Pharmacodynamic properties

Aminosalicylic acid is bacteriostatic against Mycobacterium tuberculosis. It inhibits the onset of bacterial resistance to streptomycin and isoniazid. The mechanism of action of para-aminosalicylic acid resembles the sulfonamides, competing with paraminobenzoic acid (PABA) for dihydropteroate synthetase (DHP), a key enzyme in the biosynthesis of folates. However, para-aminosalicylic acid appears to be a weak inhibitor of DHP in vitro, raising the possibility that it may have a different target.

Pharmacokinetic properties

Absorption

aminosalicylic acid is a gastro-resistant preparation and, therefore, the acid-resistant coating of the granules protects against degradation in the stomach therefore preventing the formation of meta-aminophenol (a known hepatotoxin). The small granules are designed to escape the restriction on gastric emptying of large particles. Under neutral conditions 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.

Because the 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 stools.

In a single dose (4 grams) pharmacokinetic study in healthy adult volunteers (N=11) the initial time to a 2 µg/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 35µg/mL: a level of 2 µg/mL was maintained for an average of 8 hours with a range of 5 to 9.5 a level of 1 µg/mL was maintained for an average of 8.8 hours with a range of 6 to 11.5 hours.

Distribution

Para-aminosalicylic acid is distributed in various tissues and fluids including the lungs, kidneys, liver and peritoneal fluid. Pleural or synovial fluid concentrations are approximately equal to plasma. The drug does not cross the blood brain barrier in patients unless the meninges are inflamed, when the concentration of para-aminosalicylic acid in cerebrospinal fluid is about 10 to 50% of the plasma. It is unknown whether it passes through the placental barrier. Small amounts of this agent are distributed in the milk and bile.
Plasma protein binding is about 50 to 60%, the kinetic distribution has a half-life of 0.94 hours and a volume of distribution of 1.001 L/kg.

Biotransformation

Para-aminosalicylic acid is acetylated in the liver and converted into the inactive metabolite, N-acetylpara-aminosalicylic acid which is devoid of bacteriostatic activity. The plasma half-life of this agent is about 1 hour, the concentration is not substantially altered in hepatic dysfunction. The concentration of the metabolite may be increased in cases of renal failure.
The major metabolites of PAS are produced by conjugation to glycine in para-aminosalicyluric acid (PASU) for up to 25% of the dose and to N-acetyl in N-acetyl para-aminosalicylic acid (Ac-PAS) for up to 70% of the dose. Together they constitute more than 90% of the total metabolites of PAS found in urine.

Elimination

In a single dose study the plasma half-life of para-aminosalicylic acid administered as aminosalicylic acid was 1.62 ± 0.85 h. Para-aminosalicylic acid and its metabolites are excreted by glomerular filtration and tubular secretion.

The cumulative excretion of para-aminosalicylic after 24 hours is 84% of an oral dose of 4 g, 21% as para-aminosalicylic acid and 63% as the acetylated form. The acetylation process is not genetically determined as is the case for isoniazid.

Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and repeated dose toxicity.

The data available from a rat embryofoetal development study, where animals were given sodium aminosalicylate (3.85 to 385 mg/kg) were limited. Bone defects were observed at 77 mg/kg only.and increased foetal weight was noted at the other doses. Other malformations were observed; however, the exact nature of these findings is unknown. The lack of a dose-response relationship suggests that the findings are not of clinical relevance, but it is noted that the findings were observed at doses below those proposed clinically. In the rabbit, sodium aminosalicylate had no effects on embryofoetal development; however, the doses evaluated were below those proposed clinically.

Sodium aminosalicylic acid was not mutagenic in Ames test strain TA 100. In human lymphocyte cultures in-vitro clastogenic effects of achromatic, chromatid, isochromatic breaks or chromatid translocations were not seen at 153 or 600 µg /mL but at 1500 and 3000 µg /mL there was a dose related increase in chromatid aberrations. An in vivo genotoxicity study (micronucleus test) has been conducted with aminosalicylic acid. Results indicate that aminosalicylic acid was considered not to have produced any clastogenic effect in mice treated at non-toxic dose levels (examined 24 hours after 2 daily administrations of 312.5 to 1250 mg/kg).

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