P2 receptor; CYP2; CYP3; adenosine diphosphate/ADP receptor

Ticlopidine displays activity at apparent Ki,app values of 14 µM against human CD39[1]. Ticlopidine has a Ki value of 127±12 µM, which inhibits recombinant human CD39 expressed in COS-7-cells[1]. Ticlopidine (30 and 150 µM) has an impact on growth rate in the first few days of culture, but its effects diminish in the days that follow[4].

Ticlopidine can effectively prevent losartan metabolism in the intestine and/or liver when given orally in combination with Losartan at a dose of 10 mg/kg. This is indicated by the considerable rise in the AUC (by 65.0%) observed by this combination[3].

Ticlopidine is an effective inhibitor of platelet aggregation. It is a prodrug that is metabolised to an active form, which blocks the ADP receptor that is involved in GPIIb/IIIa receptor activation leading to platelet aggregation. Ticlopidine is marketed under the brand name Ticlid and is indicated for patients who cannot take aspirin or in whom aspirin has not worked to prevent a thrombotic stroke. The FDA label includes a black-box warning of neutropenia, aplastic anemia, thrombotic thrombocytopenia purpura, and agranulocytosis, so it is necessary to monitor patients' WBC and platelets when they are taking ticlopidine.

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Ticlopidine Hydrochloride is the hydrochloride salt form of ticlopidine, a thienopyridine derivative with anticoagulant property. Ticlopidine hydrochloride irreversibly inhibits adenosine-diphosphate (ADP)-induced platelet-fibrinogen binding by binding to the glycoprotein (GP) IIb/IIIA complex, one of the two purinergic receptors activated by ADP. Inhibition of the receptor activation causes the inhibition of adenylyl cyclase, results in decreased levels of cyclic adenosine monophosphate and thereby interferes with platelet membrane function and subsequent, platelet-platelet interaction, release of platelet granule constituents and prolongation of bleeding time.

Cell Proliferation Assay[4]
Cell Types: Human endothelial cells
Tested Concentrations: 30 and 150 µM
Incubation Duration: 2, 6; 10 days
Experimental Results: Treated cells grow slower if compared with controls and this effect correlates with the concentration of Ticlopidine in the culture medium.

Animal/Disease Models: Male SD (Sprague-Dawley) rats ( 7-8 weeks old, weighing 270-300 g)[3]
Doses: 4 or 10 mg/kg
Route of Administration: Orally administered 30 min before oral administration of losartan.
Experimental Results: The AUC and Cmax of Losartan after oral administration with Losartan and 10 mg/kg Ticlopidine were Dramatically greater (by 65.0% and 49.4%, respectively) than those of control rats.

Absorption, Distribution and Excretion
Absorption is greater than 80%. Food increases absorption by approximately 20%.
Ticlopidine is eliminated mostly in the urine (60%) and somewhat in the feces (23%).
The volume of distribution was not quantified.
Ticlopidine clearance was not quantified, but clearance decreases with age.

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Metabolism / Metabolites
Ticlopidine is metabolized extensively by the liver with only trace amounts of intact drug detected. At least 20 metabolites have been identified.
Ticlopidine has known human metabolites that include Ticlopidine S-oxide and Thienodihydropyridinium.

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Biological Half-Life
Half-life following a single 250-mg dose is approximately 7.9 hours in subjects 20 to 43 years of age and 12.6 hours in subjects 65 to 76 years of age. With repeated dosing (250 mg twice a day), half-life is about 4 days in subjects 20 to 43 years of age and about 5 days in subjects 65 to 76 years of age.

Hepatotoxicity
Ticlopidine has been associated with serum enzyme elevations in approximately 4% of patients during therapy. These elevations are usually mild, asymptomatic and rarely require dose modification or stopping. Ticlopidine has also been associated with clinically apparent, acute liver injury. While these reactions are rare, more than 50 instances have been reported in the literature and some have been severe. The onset of symptoms is typically within 6 weeks (range 1 to 24 weeks) and marked by onset with fatigue, jaundice and itching. The usual pattern of liver enzyme elevations is cholestatic (~75%), but cases with mixed or hepatocellular enzyme elevations have also been described. Immunoallergic features such as fever, rash and eosinophilia can occur but are not common and, if present, are usually mild. Autoantibody formation is rare. Liver biopsy usually shows cholestatic hepatitis with mixed cellular infiltrates. Most cases are self-limited with recovery within 1 to 3 months, but isolated cases of prolonged jaundice or liver test abnormalities have been described, including at least one case of probable vanishing bile duct syndrome that eventually required liver transplantation. Ticlopidine therapy has also been associated with aplastic anemia and thrombotic thrombocytopenic purpura (TTP) that can be severe and lead to death; these patients may also have accompanying cholestatic liver injury.

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Protein Binding
Binds reversibly (98%) to plasma proteins, mainly to serum albumin and lipoproteins. The binding to albumin and lipoproteins is nonsaturable over a wide concentration range. Ticlopidine also binds to alpha-1 acid glycoprotein (about 15% or less).

[1]. 2-Substituted thienotetrahydropyridine derivatives: Allosteric ectonucleotidase inhibitors. Arch Pharm (Weinheim). 2021 Dec;354(12):e2100300.

[2]. Ticlopidine-Induced Cholestatic Inflammatory Hepatitis: New Insights into Pathogenetic Mechanisms of Drug-Related Hepatotoxicity.

[3]. Effects of ticlopidine on pharmacokinetics of losartan and its main metabolite EXP-3174 in rats. Acta Pharmacol Sin. 2011 Jul;32(7):967-72.

[4]. The effect of Ticlopidine on human endothelial cells in culture. Thromb Res. 1984 Feb 1;33(3):323-32.

Ticlopidine is a thienopyridine that is 4,5,6,7-tetrahydrothieno[3,2-c]pyridine in which the hydrogen attached to the nitrogen is replaced by an o-chlorobenzyl group. It has a role as a fibrin modulating drug, a hematologic agent, an anticoagulant, a platelet aggregation inhibitor and a P2Y12 receptor antagonist. It is a thienopyridine and a member of monochlorobenzenes.
Ticlopidine is an effective inhibitor of platelet aggregation. It is a prodrug that is metabolised to an active form, which blocks the ADP receptor that is involved in GPIIb/IIIa receptor activation leading to platelet aggregation. Ticlopidine is marketed under the brand name Ticlid and is indicated for patients who cannot take aspirin or in whom aspirin has not worked to prevent a thrombotic stroke. The FDA label includes a black-box warning of neutropenia, aplastic anemia, thrombotic thrombocytopenia purpura, and agranulocytosis, so it is necessary to monitor patients' WBC and platelets when they are taking ticlopidine.
Ticlopidine is a Platelet Aggregation Inhibitor. The physiologic effect of ticlopidine is by means of Decreased Platelet Aggregation.
Ticlopidine is an inhibitor of platelet aggregation that is used to decrease the risk of stroke in patients known to have atherosclerosis. Ticlopidine is associated with a low rate of serum enzyme elevations during treatment and has been linked to rare instances of idiosyncratic, clinically apparent acute liver injury.
Ticlopidine is a thienopyridine derivative with anticoagulant activity. Ticlopidine inhibits adenosine-diphosphate (ADP) binding to its platelet receptor. This prevents ADP activation and inhibits platelet expression of the glycoprotein (GP) IIb/IIIA receptors, binding of fibrinogen to platelet glycoprotein GP IIb-IIIa and platelet-platelet interaction. This results in increased bleeding time.
An effective inhibitor of platelet aggregation commonly used in the placement of STENTS in CORONARY ARTERIES.
See also: Ticlopidine Hydrochloride (has salt form).

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Drug Indication
Used in patients, who have had a stroke or stroke precursors and who cannot take aspirin or aspirin has not worked, to try to prevent another thrombotic stroke.
FDA Label

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Mechanism of Action
The active metabolite of ticlopidine prevents binding of adenosine diphosphate (ADP) to its platelet receptor, impairing the ADP-mediated activation of the glycoprotein GPIIb/IIIa complex. It is proposed that the inhibition involves a defect in the mobilization from the storage sites of the platelet granules to the outer membrane. No direct interference occurs with the GPIIb/IIIa receptor. As the glycoprotein GPIIb/IIIa complex is the major receptor for fibrinogen, its impaired activation prevents fibrinogen binding to platelets and inhibits platelet aggregation. By blocking the amplification of platelet activation by released ADP, platelet aggregation induced by agonists other than ADP is also inhibited by the active metabolite of ticlopidine.

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Pharmacodynamics
Ticlopidine is a prodrug that is metabolised to an as yet undetermined metabolite that acts as a platelet aggregation inhibitor. Inhibition of platelet aggregation causes a prolongation of bleeding time. In its prodrug form, ticlopidine has no significant in vitro activity at the concentrations attained in vivo.

C14H14CLNS

263.79

263.053

55142-85-3

Ticlopidine hydrochloride;53885-35-1;Ticlopidine-d4;1246817-49-1

5472

Light yellow to yellow oil

1.3±0.1 g/cm3

367.3±37.0 °C at 760 mmHg

approx. 1 189°C

175.9±26.5 °C

0.0±0.8 mmHg at 25°C

1.638

3.77

0

2

2

17

261

0

PHWBOXQYWZNQIN-UHFFFAOYSA-N

InChI=1S/C14H14ClNS/c15-13-4-2-1-3-11(13)9-16-7-5-14-12(10-16)6-8-17-14/h1-4,6,8H,5,7,9-10H2

5-[(2-chlorophenyl)methyl]-6,7-dihydro-4H-thieno[3,2-c]pyridine

5-(2-Chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine; Ticlopidina; Ticlopidinum; Ticlopidin-Puren; PCR 5332; Ticlopidinum [INN-Latin];

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

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 (379.09 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (9.48 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 2: ≥ 2.5 mg/mL (9.48 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.)