Absorption, Distribution and Excretion
BIOAVAILABILITY STUDIES ON P-AMINOSALICYLIC ACID & ITS SALTS IN 12 SUBJECTS. COLORIMETRIC ASSAY INDICATED THAT PEAK BLOOD LEVELS OCCURRED @ 0.5, 0.75, 1.5, & 3 HR FOR SODIUM, POTASSIUM, & CALCIUM SALTS & P-AMINOSALICYLIC ACID, RESPECTIVELY.
URINE EXCRETION DATA SHOWED ABSORPTION TO BE ESSENTIALLY COMPLETE ALTHOUGH RATES OF ABSORPTION DIFFERED.
Aminosalicyclic acid is readily absorbed from the gastrointestinal tract. A single oral dose of 4 g of the free acid produces maximal concentrations in plasma of about 75 ug/ml within 1.5 to 2 hours. The sodium salt is absorbed even more rapidly. The drug appears to be distributed throughout the total body water and reaches high concentrations in pleural fluid and caseous tissue. However, values in CSF are low, perhaps because of active outward transport.
Over 80% of the drug is excreted in the urine; more than 50% is in the form of the acetylated compound. The largest portion of the remainder is made up of the free acid.
For more Absorption, Distribution and Excretion (Complete) data for P-AMINOSALICYLIC ACID (8 total), please visit the HSDB record page.

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Metabolism / Metabolites
Hepatic.
ACETYLATION IS MAJOR ROUTE FOR INACTIVATION OF MANY DRUGS SUCH AS ... P-AMINOSALICYLIC ACID... ENZYMES WHICH CATALYSE THESE REACTIONS, ACETYL COENZYME A:N-ACETYLTRANSFERASES (EC2.3.1.5), ARE LOCATED IN LIVER CYTOSOL.
WHEN ADMIN ORALLY TO MAN IT IS RAPIDLY ABSORBED, & IS EXCRETED IN URINE AS UNCHANGED P-AMINOSALICYLIC ACID & AS ACETYL GLUCURONYL, GLYCYL & GLUTAMINYL CONJUGATES.
YIELDS 5-AMINO-2-CARBOXYPHENYL-BETA-D-GLUCURONIDE IN MAN. 4-AMINOCATECHOL IN PSEUDOMONAS. 4-AMINOSALICYLOYLGLUTAMINE & 4-AMINOSALICYLOYLGLYCINE IN MAN. /TABLE/
Blood from tuberculosis patients was cultured before, during, and after withdrawal of therapy involving five different drug combinations if isoniazid, thiacetazone, p-aminosalicyclic acid, and streptomycin. The approaches used to detect DNA damage were chromosome aberrations and sister chromatid exchanges (SCEs). A total of 179 subjects were analyzed. In combo these drugs showed synergistic, additive, and antagonistic effects, though they were found to be nonclastogenic individually. Four of the drug combinations, isoniazid plus thiacetazone, isoniazid plus p-aminosalicyclic acid, isoniazid plus thiacetazone plus streptomycin, and isoniazid plus p-aminosalicyclic acid plus streptomycin, induced a significant incr in the frequency of aberrations, whereas isoniazid plus streptomycin did not induce aberrations. In fact, streptomycin appeared to reduce the frequency of aberrations. SCEs were incr in only two patients: one treated with isoniazid plus thiacetazone and the other with isoniazid plus p-aminosalicyclic acid. The frequency of aberrations after withdrawal of therapy was decr; it was slightly higher than the controls, though it was insignificant. The return to normalcy could be due to elimination of damaged cells or the repair of DNA in lymphocytes. Though the drug-induced aberrations do not persist after withdrawal of therapy, the chromosome damaging combo of drugs should be used with caution, because the possibility of meiotic chromosome damage in germ cells (during therapy), which might be passed on to the next generation, cannot be ruled out.
For more Metabolism/Metabolites (Complete) data for P-AMINOSALICYLIC ACID (9 total), please visit the HSDB record page.

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Biological Half-Life
The drug has a half life of about 1 hour, and concentrations in plasma are negligible within 4 to 5 hours after a single conventional dose.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Limited information indicates that maternal aminosalicylic acid therapy produces low levels in milk and would not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months. Exclusively breastfed infants should be monitored for rare instances of jaundice, gastrointestinal disturbances, hypokalemia, thrombocytopenia, hemolysis and hypokalemia if this drug is used during lactation.
◉ Effects in Breastfed Infants
Aminosalicylic acid was used as part of multi-drug regimens to treat 2 pregnant women with multidrug-resistant tuberculosis throughout pregnancy and postpartum. Their two infants were breastfed (extent and duration not stated). At age 1.8 and 4.6 years, the children were developing normally, except for except for a mild speech delay in one at age 1.8 years, and failure to thrive in the other, possibly due to tuberculosis contracted after birth.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
50-60%

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Interactions
...PARA-AMINOSALICYLIC ACID.../INHIBITS METABOLISM OF CHLORAMPHENICOL/
PENTOBARBITAL /SRP: CNS DEPRESSION/ IN MICE WAS ENHANCED AFTER PRE-TREATMENT WITH... P-AMINOSALICYLIC ACID. INCR /SRP: CNS DEPRESSION/ APPEARED TO BE DUE TO RELEASE OF PENTOBARBITAL FROM SERUM-PROTEIN BINDING, RESULTING IN HIGHER CEREBRAL CONCN...
ADDITIVE & SYNERGISTIC WITH STREPTOMYCINS & ISONIAZID.
Probenecid decreases the renal excretion of this agent.
For more Interactions (Complete) data for P-AMINOSALICYLIC ACID (19 total), please visit the HSDB record page.

4-aminosalicylic acid is an aminobenzoic acid that is salicylic acid substituted by an amino group at position 4. It has a role as an antitubercular agent. It is an aminobenzoic acid and a member of phenols. It is functionally related to a salicylic acid. It is a conjugate acid of a 4-aminosalicylate(1-).
An antitubercular agent often administered in association with isoniazid. The sodium salt of the drug is better tolerated than the free acid.
Aminosalicylic Acid is an analog of para-aminobenzoic acid (PABA) with antitubercular activity. Aminosalicylic acid exerts its bacteriostatic activity against Mycobacterium tuberculosis by competing with PABA for enzymes involved in folate synthesis, thereby suppressing growth and reproduction of M. tuberculosis, eventually leading to cell death.
Aminosalicylate Sodium is the sodium salt form of aminosalicylic acid, an analog of para-aminobenzoic acid (PABA) with antitubercular activity. Aminosalicylate sodium exerts its bacteriostatic activity against Mycobacterium tuberculosis by competing with PABA for enzymes involved in folate synthesis, thereby suppressing growth and reproduction of M. tuberculosis, eventually leading to cell death.
An antitubercular agent often administered in association with ISONIAZID. The sodium salt of the drug is better tolerated than the free acid.

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Drug Indication
For the treatment of tuberculosis
Granupas is indicated for use as part of an appropriate combination regimen for multi-drug resistant tuberculosis in adults and paediatric patients from 28 days of age and older when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability (see section 4. 4). Consideration should be given to official guidance on the appropriate use of antibacterial agents.

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Mechanism of Action
There are two mechanisms responsible for aminosalicylic acid's bacteriostatic action against Mycobacterium tuberculosis. Firstly, aminosalicylic acid inhibits folic acid synthesis (without potentiation with antifolic compounds). The binding of para-aminobenzoic acid to pteridine synthetase acts as the first step in folic acid synthesis. Aminosalicylic acid binds pteridine synthetase with greater affinity than para-aminobenzoic acid, effectively inhibiting the synthesis of folic acid. As bacteria are unable to use external sources of folic acid, cell growth and multiplication slows. Secondly, aminosalicylic acid may inhibit the synthesis of the cell wall component, mycobactin, thus reducing iron uptake by M. tuberculosis.
The antimicrobial activity of aminosalicylic acid is highly specific, and microorganisms other than Mycobacterium tuberculosis are unaffected. Most nontuberculous mycobacteria are not inhibited by the drug.
Aminosalicyclic acid is a structural analog of paraaminobenzoic acid, and its mechanism of action appears to be very similar to that of the sulfonamides. Since the sulfonamides are ineffective against Mycobacterium tuberculosis, and aminosalicyclic is inactive against sulfonamide susceptible bacteria, it is probable that the enzymes responsible for folate biosynthesis in various microorganisms may be quite exacting in their capacity to distinguish various analogs from the true metabolite.

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Therapeutic Uses
Antitubercular Agents
EXPTL USE: LIPID LOWERING AGENT. 6 G GIVEN FOR 4 WK. IT WAS CONCLUDED THAT IT LOWERS ELEVATED SERUM TRIGLYCERIDE LEVELS AS WELL AS ELEVATED SERUM CHOLESTEROL LEVELS.
USED ALONE, IT CAN SOMETIMES SUCCESSFULLY MANAGE /TUBERCULOSIS/...BUT RESISTANCE EMERGES & ALSO TOXICITY LIMITS THE DOSE. THEREFORE, PAS IS NEARLY ALWAYS USED IN COMBINATION WITH 1 OR 2 OTHER ANTITUBERCULAR DRUGS. ...PAS SUPPORTS THE OTHER DRUGS & DELAYS THE EMERGENCY OF RESISTANCE.
AMINOSALICYLIC ACID...HAS POTENT HYPOLIPIDEMIC ACTION & REDUCES BOTH CHOLESTEROL & TRIGLYCERIDES. HOWEVER IT HAS NOT BEEN WELL TOLERATED BECAUSE OF GI REACTION.
For more Therapeutic Uses (Complete) data for P-AMINOSALICYLIC ACID (15 total), please visit the HSDB record page.

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Drug Warnings
UNDER NO CIRCUMSTANCES USE SOLN IF ITS COLOR IS DARKER THAN THAT OF FRESHLY PREPD SOLN. ... PREPARE SOLN OF CALCIUM, /POTASSIUM, & SODIUM SALTS/ WITHIN 24 HR OF ADMIN.
FOR THE VARIOUS DEFECTS /FOR EXAMPLE, DEFICIENCY IN ERYTHROCYTE GLUCOSE-6-PHOSPHATE DEHYDROGENASE/ THAT SEEM TO BE SPECIFIC TO PARTICULAR RACES, DIFFERENT DRUGS ELICIT HEMOLYSIS. MOST IMPORTANT OF THESE ARE NITROFURANTOIN, AMINOSALICYLIC ACID...
IN PT WITH IMPAIRMENT OF KIDNEY OR OTHER MECHANISMS FOR CONTROLLING PLASMA CONCN, THE DRUG CAN CAUSE HYPERCALCEMIA. IT MAY ALSO CONTRIBUTE TO UROLITHIASIS. /CA SALT/
The most frequent adverse effects of aminosalicylic acid or its salt are GI disturbances including nausea, vomiting, abdominal pain, diarrhea, and anorexia. Rarely, aminosalicylic acid has caused peptic ulcer and gastric hemorrhage. Adverse GI effects may be minimized in some patients by administering the aminosalicylates with meals; however, symptoms may be severe enough to require discontinuation of the drugs. Malabsorption of vitamin B12 folic acid, iron, and lipids has also occurred occasionally in patients receiving aminosalicylic acid or its salt, possibly as the result of increased peristalsis. The manufacturer states that maintenance therapy with vitamin B12 should be considered in patients receiving aminosalicylic acid for longer than 1 month.
For more Drug Warnings (Complete) data for P-AMINOSALICYLIC ACID (12 total), please visit the HSDB record page.

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Pharmacodynamics
Aminosalicylic acid is an anti-mycobacterial agent used with other anti-tuberculosis drugs (most often isoniazid) for the treatment of all forms of active tuberculosis due to susceptible strains of tubercle bacilli. 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. Aminosalicylic acid is bacteriostatic against Mycobacterium tuberculosis (prevents the multiplying of bacteria without destroying them). It also inhibits the onset of bacterial resistance to streptomycin and isoniazid.

C7H7NO3

153.1354

153.042

65-49-6

Sodium 4-aminosalicylate dihydrate;6018-19-5;4-Aminosalicylic acid hemicalcium;133-15-3

4649

MINUTE CRYSTALS FROM ALC
WHITE, OR NEARLY WHITE, BULKY POWDER
NEEDLES, PLATES FROM ALC-ETHER
A reddish-brown crystalline powder is obtained on recrystallization from ethanol-ether.

1.5±0.1 g/cm3

380.8±32.0 °C at 760 mmHg

135-145 °C(lit.)

184.1±25.1 °C

0.0±0.9 mmHg at 25°C

1.691

1.14

3

4

1

11

160

0

O([H])C1C([H])=C(C([H])=C([H])C=1C(=O)O[H])N([H])[H]

WUBBRNOQWQTFEX-UHFFFAOYSA-N

InChI=1S/C7H7NO3/c8-4-1-2-5(7(10)11)6(9)3-4/h1-3,9H,8H2,(H,10,11)

4-amino-2-hydroxybenzoic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~653.00 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (16.32 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (16.32 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (16.32 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)