Between sustained-release dipyridamole pellets and acetylsalicylic acid, there is no significant pharmacokinetic interaction. Therefore, the pharmacokinetics of the drug AGRENOX is characterized by the pharmacokinetics of the individual components.
Dipyridamole
Most of the data on pharmacokinetics was obtained in studies on healthy volunteers.
Dipyridamole is characterized by a linear dependence of the pharmacokinetics on the applied dose.
For long-term treatment with dipyridamole, modified-release capsules have been developed, which include pellets. Dependence of the solubility of dipyridamole on pH, preventing the dissolution of dipyridamole in the lower gastrointestinal tract (where sustained release preparations still have to release the active substance), was overcome by its combination with tartaric acid. Delayed release is achieved through the use of a diffusion membrane, which is sprayed onto pellets as a spray. Various kinetic studies in the equilibrium state have shown that according to the pharmacokinetic parameters characterizing the modified release preparations,Dipiridamole capsules with modified release, which are taken 2 times a day, are either equivalent, or by some parameters, superior to dipyridamole tablets, which take 3-4 times a day. Bioavailability is slightly higher, the maximum concentrations are the same, the concentrations between receptions are much higher, fluctuations in peak concentrations between receptions are reduced.
Suction
Absolute bioavailability is about 70%. Since at the primary passage about 1/3 of the dose administered is removed, we can assume almost or complete absorption of dipyridamole after taking the drug.
The maximum concentration of dipyridamole in the plasma after taking a daily dose of 400 mg (200 mg twice a day) is observed 2-3 hours after taking the drug. The mean maximum concentrations at the equilibrium state are 1.98 μg / ml (range 1.01 to 3.99 μg / ml) and the concentrations between the receipts are 0.53 μg / ml (range 0.18-1.01 μg / ml) .
Food intake does not affect the pharmacokinetics of dipyridamole in the preparation AGRENOX
Distribution
Due to its high lipophilicity, log P 3.92 (p-octanol / 0.1 p, NaOH), Dipyridamole is distributed in many organs.
In animals dipyridamole mainly distributed in the liver, as well as in the lungs, kidneys, spleen and heart.
The rapid phase of the distribution observed with intravenous administration can not be determined by oral administration.
The apparent volume of distribution in the central compartment (Vc) is about 5 liters (similar to the volume of the plasma). The apparent volume of the distribution at the equilibrium state is about 100 liters, reflecting the distribution in different compartments. The drug does not penetrate the blood-brain barrier in a significant amount. Penetration of the drug through the placental barrier is very low.
In one case, breast milk was found to contain an amount of 1/17 of its concentration in the plasma.
The binding of dipyridamole with proteins is about 97% -99%, mainly it binds to alpha-1-acid glycoprotein and albumin.
Metabolism
The metabolism of dipyridamole occurs in the liver. Dipyridamole is mainly metabolized by conjugation with glucuronic acid with the formation of mainly monoglycuronide and only small amounts of diglucuronide. In plasma, about 80% of the total is present in the form of the starting compound, and 20% of the total amount in the form of monoglycuronide.The pharmacodynamic activity of dipyridamole glucuronides is significantly lower than that of dipyridamole.
Excretion
The dominant half-life for oral administration, as for intravenous administration, is about 40 minutes.
Excretion of the drug unchanged through the kidneys is negligible (<0.5%). Excretion of the metabolite glucuronide in the urine is low (5%), metabolites are mainly (about 95%) excreted through bile with feces, while intestinal-hepatic recirculation is observed. The total clearance is about 250 ml / min, the average residence time in the body is about 11 hours determined on the basis of its own average residence time in the body of about 6.4 hours and an average suction time of 4.6 hours).
As with intravenous administration, a prolonged period of final half-life is observed, which is about 13 hours. This final elimination phase has a relatively small value, since it is an insignificant part of the total area under the pharmacokinetic curve (AUC), which is confirmed by the fact that when receiving capsules with a modified release 2 times a day, the equilibrium state is reached within 2 days.
With repeated administration of a dose, no appreciable accumulation of the drug is observed.
Kinetics in the elderly
The concentrations of dipyridamole in plasma (determined by AUC) in the elderly (> 65 years) were approximately 50% higher for tablets and about 30% higher for capsules with a modified release of AGRENOX than for young (<55 years) subjects. This difference is mainly due to reduced clearance, because it turned out that the intake was the same.
Kinetics in patients with renal insufficiency
Due to low deducing through the kidneys (5%), it can be assumed that there is no change in pharmacokinetics in the case of kidney failure. In the study ESPS2 in patients with a creatinine clearance in the range of about 15 ml / min and up to> 100 ml / min, changes in the pharmacokinetics of dipyridamole or its metabolite-glucuronide dipyridamole - were not observed provided that the data were adjusted to the age difference.
Kinetics in patients with hepatic impairment
In patients with hepatic insufficiency, there was no change in plasma dipyridamole concentrations, but an increase in glucuronide concentrations with low pharmacodynamic activity was noted. Therefore, adjusting the dose of dipyridamole is necessary only in the case of clinically confirmed decompensation of liver function.
Acetylsalicylic acid
Suction
Acetylsalicylic acid is rapidly and completely absorbed. Maximum plasma concentrations after taking a daily dose of 50 mg of acetylsalicylic acid in the preparation of AGRENOX (25 mg twice daily) are observed after 30 minutes, and the maximum plasma concentration in the equilibrium state is 319 ng / ml (range 175-463 ng / ml). Maximum concentrations of salicylic acid in plasma are reached after 60-90 minutes.
30-40% of the dose of acetylsalicylic acid undergoes primary metabolism with cleavage to salicylic acid, which is the main pathway of metabolism. Pharmacodynamics of acetylsalicylic acid in the composition of AGRENOX does not depend on the intake of food.
Distribution
Acetylsalicylic acid poorly binds to plasma proteins, and its apparent volume of distribution is small (10 liters). Metabolite of acetylsalicylic acid - salicylic acid largely binds to plasma proteins, but binding depends on concentration (non-linearly). At low concentrations (<100 μg / ml), about 90% of salicylic acid is bound to albumin. Salicylic acid is well distributed in all tissues and body fluids, including the central nervous system, breast milk and fetal tissues.
Metabolism
Acetylsalicylic acid is rapidly metabolized by the action of nonspecific esterases in the liver, and to a lesser extent in the stomach to salicylic acid, followed by the formation of hydroxyhippuric acid as a result of the reaction with glycine.
Excretion
The half-life of acetylsalicylic acid is 15-20 minutes; the half-life of the main metabolite (salicylic acid) is 2-3 hours, can increase to 5-18 hours at high doses (> 3 g) because of the saturation of the enzyme.
About 90% of acetylsalicylic acid is excreted in the form of metabolites through the kidneys.
Kinetics in patients with renal insufficiency
In severe disturbances of kidney function (glomerular filtration rate less than 10 ml / min), acetylsalicylic acid should not be administered.
An increase in the half-life of 2-3 times in patients with kidney disease has been reported.
Kinetics in patients with hepatic impairment
With severe liver failure, acetylsalicylic acid should not be prescribed.