Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antimycobacterials, drugs for treatment of tuberculosis.
ATC code: J04AA01

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 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

5.2 Pharmacokinetic properties

Absorption
GRANUPAS 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 35 µg/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-acetyl- para-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 GRANUPAS 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.