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Pharmacology: Pharmacodynamics: Tranexamic acid is a competitive inhibitor of plasminogen activation, and at much higher concentrations, a noncompetitive inhibitor of plasmin, i.e., actions similar to aminocaproic acid. Tranexamic acid is about 10 times more potent in vitro than aminocaproic acid.
Tranexamic acid binds more strongly than aminocaproic acid to both the strong and weak receptor sites of the plasminogen molecule in a ratio corresponding to the difference in potency between the compounds. Tranexamic acid in a concentration of 1 mg/mL does not aggregate platelets in vitro.
Tranexamic acid in concentrations up to 10 mg/mL blood has no influence on the platelet count, the coagulation time or various coagulation factors in whole blood or citrated blood from normal subjects. However, tranexamic acid in concentrations as low as 1 mg per mL can prolong the thrombin time.
Pharmacokinetics: The plasma protein binding of tranexamic acid is about 3% at therapeutic plasma levels and seems to be fully accounted for by its binding to plasminogen. Tranexamic acid does not bind to serum albumin.
After an intravenous dose of 1 g, the plasma concentration time curve shows a triexponential decay with a half-life of about 2 hours for the terminal elimination phase. The initial volume of distribution is about 9 to 12 liters. Urinary excretion via glomerular filtration is the main route of elimination. Overall renal clearance is equal to overall plasma clearance (110 to 116 mL/min) and more than 95% of the dose is excreted in the urine as the unchanged drug. Excretion of tranexamic acid is about 90% at 24 hours after intravenous administration of 10 mg/kg body weight.
An antifibrinolytic concentration of tranexamic acid remains in different tissues for about 17 hours, and in the serum, up to 7 or 8 hours.
Tranexamic acid passes through the placenta. The concentration in cord blood after an intravenous injection of 10 mg/kg to pregnant women is about 30 mg/L, as high as in the maternal blood. Tranexamic acid diffuses rapidly into joint fluid and the synovial membrane. In the joint fluid the same concentration is obtained as in the serum. The biological half-life of tranexamic acid in the joint fluid is about 3 hours.
The concentration of tranexamic acid in a number of other tissues is lower than in blood. In breast milk the concentration is about one hundredth of the serum peak concentration.
Tranexamic acid concentration in cerebrospinal fluid is about one tenth of that of the plasma.
The drug passes into the aqueous humor, the concentration being about one tenth of the plasma concentration.
Tranexamic acid has been detected in semen where it inhibits fibrinolytic activity but does not influence sperm migration.
Toxicology: Preclinical safety data: An increased incidence of leukemia in male mice receiving tranexamic acid in food at a concentration of 4.8% (equivalent to doses as high as 5 g/kg/day) may have been related to treatment. Female mice were not included in this experiment.
Hyperplasia of the biliary tract and cholangioma and adenocarcinoma of the intrahepatic biliary system have been reported in one strain of rats after dietary administration of doses exceeding the maximum tolerated dose for 22 months. Hyperplastic, but not neoplastic, lesions were reported at lower doses. Subsequent long-term dietary administration studies in a different strain of rat, each with an exposure level equal to the maximum level employed in the earlier experiment, have failed to show such hyperplastic/neoplastic changes in the liver.
No mutagenic activity has been demonstrated in several in vitro and in vivo genotoxicity testing systems.
In published, pre-clinical animal studies, epileptic activities were induced by topical application of tranexamic acid to the cortex of anesthetized cats. Similarly, intravenous infusion of high doses (500-600 mg/kg) of tranexamic acid induced seizure-like activity in conscious cats. Severe hind limb spasms developed into generalized convulsions in a rat model following application of tranexamic acid to the lumbar spinal cord. Tranexamic acid within a fibrin sealant similarly induced limb spasms and convulsions in this rat model.
Fibrin sealant containing tranexamic acid evoked generalized seizures in rats following application to the cerebral cortex of anesthetized rats. CNS hyperexcitability may be the result of antagonism of γ-aminobutyric acidA receptors by tranexamic acid.
