Source: Υπουργείο Υγείας (CY) Revision Year: 2015 Publisher: MEDOCHEMIE LTD, 1-10 Constantinoupoleos street, 3011 Limassol, Cyprus
Pharmacotherapeutic group: Platelet aggregation inhibitors excl. heparin, Antithrombotic agents
ATC code: B01AC07
Dipyridamole inhibits the uptake of adenosine into erythrocytes, platelets and endothelial cells in vitro and in vivo; the inhibition amounts to 80% at its maximum and occurs dose-dependently at therapeutic concentrations (0.5-2 µg/mL). Consequently, there is an increased concentration of adenosine locally to act on the platelet A2-receptor, stimulating platelet adenylate cyclase, thereby increasing platelet cAMP levels. Thus, platelet aggregation in response to various stimuli such as PAF, collagen and ADP is inhibited. Reduced platelet aggregation reduces platelet consumption towards normal levels. In addition, adenosine has a vasodilator effect and this is one of the mechanisms by which dipyridamole produces vasodilation.
Dipyridamole inhibits phosphodiesterase (PDE) in various tissues. Whilst the inhibition of cAMP-PDE is weak, therapeutic levels inhibit cGMP-PDE, thereby augmenting the increase in cGMP produced by EDRF (endothelium-derived relaxing factor, identified as NO).
Dipyridamole also stimulates the biosynthesis and release of prostacyclin by the endothelium.
Dipyridamole reduces the thrombogenicity of subendothelial structures by increasing the concentration of the protective mediator 13-HODE (13-hydroxyoctadecadienic acid)
After dosing with the sugar-coated tablets there is a lag time of 10-15 min associated with disintegration of the tablet and gastric emptying. Thereafter the drug is rapidly absorbed and peak plasma concentrations are attained after 1 hour. Geometric mean (range) peak plasma concentrations at steady state conditions with 75 mg t.d.s. were 1.86 µg/mL (1.23-3.27 µg/mL), and at trough were 0.13 µg/mL (0.06-0.26 µg/mL). With 75 mg q.i.d. corresponding peak concentrations were 1.54 µg/mL (0.975-2.17 μg/mL), trough concentrations were 0.269 µg/mL (0.168-0.547 µg/mL). With 100 mg q.i.d. corresponding peak concentrations were 2.36 µg/mL (1.13-3.81 µg/mL), trough concentrations were 0.432 µg/mL (0.186-1.38 µg/mL). The dose linearity of dipyridamole after single dose administration was demonstrated in the range from 25 to 150 mg.
Pharmacokinetic evaluations as well as experimental results in steady state conditions indicate that t.d.s. or q.d.s. dosage regimens are suitable. Treatment with dipyridamole tablets at steady state provides absolute bioavailability of approx. 60% and relative bioavailability of approx. 95% compared to an orally administered solution. This is partly due to a first-pass-effect from the liver which removes approx. ⅓ of the dose administered and partly to incomplete absorption.
Owing to its high lipophilicity, log P 3.92 (n-octanol/0.1 N, NaOH), dipyridamole distributes to many organs.
Non-clinical studies indicate that, dipyridamole is distributed preferentially to the liver, then to the lungs, kidneys, spleen and heart, it does not cross the blood-brain barrier to a significant extent and shows a very low placental transfer. Non-clinical data have also shown that dipyridamole can be excreted in breast milk.
Protein binding of dipyridamole is about 97-99%; primarily it is bound to alpha 1-acid glycoprotein and albumin.
Metabolism of dipyridamole occurs in the liver. Dipyridamole is metabolized by conjugation with glucuronic acid to form mainly a monoglucuronide and only small amounts of diglucuronide. In plasma about 80% of the total amount is parent compound, 20% of the total amount is monoglucuronide with oral administration.
Dominant half-lives ranging from 2.2 to 3 hours have been calculated after the administration of PROCARDIN. A prolonged terminal elimination half-life of approximately 15 h is observed. This terminal elimination phase is of relatively minor importance in that it represents a small proportion of the total AUC, as evidenced by the fact that steady-state is achieved within 2 days with both t.d.s. and q.d.s., regimens. There is no significant accumulation of the drug with repeated dosing. Renal excretion of parent compound is negligible (<0.5%). Urinary excretion of the glucuronide metabolite is low (5%), the metabolites are mostly (about 95%) excreted via the bile into the faeces, with some evidence of entero-hepatic recirculation. Total clearance is approx. 250 mL/min and mean residence time is approx. 8 h (resulting from an intrinsic MRT of approx. 6.4 h and a mean time of absorption of 1.4 h).
Plasma concentrations (determined as AUC) in elderly subjects (>65 years) were about 50% higher for tablet treatment and about 30% higher with intake of PROCARDIN200 mg modified release capsules than in young (<55 years) subjects. The difference is caused mainly by reduced clearance; absorption appears to be similar. A similar increase in plasma concentrations in elderly patients was observed in the ESPS2 study.
Patients with hepatic insufficiency show no change in plasma concentrations of dipyridamole, but an increase of (pharmacodynamically inactive) glucuronides. It is suggested to dose dipyridamole without restriction as long as there is no clinical evidence of liver failure.
Since renal excretion is very low (5%), no change in pharmacokinetics is to be expected in cases of renal insufficiency. In the ESPS2 trial, in patients with creatinine clearances ranging from about 15 mL/min to >100 mL/min, no changes were observed in the pharmacokinetics of dipyridamole or its glucuronide metabolite if data were corrected for differences in age.
Dipyridamole has been extensively investigated in animal models and no clinically significant findings have been observed at doses equivalent to therapeutic doses in humans.
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