Clinical Pharmacokinetics of Ticlopidine

Abstract

Platelets contribute significantly to arterial-occlusive thrombosis, one of the major causes of death and disease throughout the world. Consequently, inhibiting platelet function is a potentially important therapeutic goal. Among agents that inhibit platelet function, ticlopidine shows a wide spectrum of antiplatelet activity. There have been a limited number of studies investigating the pharmacokinetic profile of the drug. However, it has been demonstrated that absorption of ticlopidine after oral administration is rapid, is improved when the drug is administered with food, but reduced by the coadministration of antacid. Ticlopidine is extensively metabolised, with little unchanged drug present in the plasma. After administration of a single dose, unchanged ticlopidine can be detected for up to 96 hours postdose. Repeated administration of ticlopidine 250mg twice daily results in 3- to 4-fold accumulation of the drug after 2 weeks. The terminal elimination half-life is between 20 and 50 hours. Dosage selection is not determined by the pharmacokinetic profile of the drug, but rather by determination of the effect of the drug on bleeding time. The clearance of theophylline and phenazone (antipyrine) are reduced by ticlopidine, resulting in increased plasma drug concentrations. In contrast, the plasma concentration of cyclosporin is reduced. Aspirin (acetylsalicylic acid) increases the bleeding time in patients receiving ticlopidine concurrently, while corticosteroids reduce bleeding time. Ticlopidine use is discouraged in patients with severe organ failure. Furthermore, ticlopidine should be discontinued 2 weeks before surgery and dental intervention. Most importantly, the blood cell count should be monitored regularly during the 3 first months of treatment with ticlopidine because 1% of patients receiving ticlopidine may experience agranulocytosis.

Mechanism-Based Inhibition of Human Cytochrome P450 2B6 by Ticlopidine, Clopidogrel, and the Thiolactone Metabolite of Prasugrel

“…However, this observation does not automatically mean that the thiolactone metabolite of ticlopidine rather than ticlopidine itself is the major player in the mechanism-based inhibition of CYP2B6 caused by ticlopidine in vivo. Because ticlopidine has been reported to be metabolized to many metabolites both in vitro (Dalvie and O'Connell 2004) and in vivo (Desager 1994), it is quite unlikely that the thiolactone metabolite of ticlopidine would reach levels higher than hepatic levels of the parent compound. Therefore, the data suggest that the mechanism-based inhibition of CYP2B6 by ticlopidine and clopidogrel in vivo mainly arises from the first oxidation step to their respective thiolactones shown in Fig.…”

Characterization of Novel Dihydrothienopyridinium and Thienopyridinium Metabolites of Ticlopidine in Vitro: Role of Peroxidases, Cytochromes P450, and Monoamine Oxidases

“…In vivo metabolic studies with ticlopidine have indicated that the principal routes of metabolism are N-dealkylation, N-oxidation, and oxidation of the thiophene ring (Tuong et al, 1981;Fraire, 1984;Desager, 1994;Noble and Goa, 1996). In vitro metabolism of ticlopidine by recombinant human P450 2C19 and 2D6 has recently led to the identification of thiophene-S-oxide dimer TSOD (M2) and 2-oxoticlopidine (M4) (see Fig.…”

Semimechanistic Population Pharmacokinetic Model to Predict the Drug–Drug Interaction Between S‐ketamine and Ticlopidine in Healthy Human Volunteers

“…After testing several absorption models, we implemented a transit‐compartmental model, which provided an adequate fit. Some reports indicate that repeated ticlopidine dosing causes an increase in its half‐life suggesting an auto‐inhibition process 12. These findings are physiologically plausible due to the marked potential of ticlopidine to inhibit CYP2B6.…”

“…Ticlopidine has a complex nonlinear pharmacokinetic profile that has been recorded previously in several reports 12. Ticlopidine is metabolized to 2‐oxo‐ticlopidine primarily in the liver by CYP2B6 and CYP2C19,13, 14 and previous studies have indicated that ticlopidine half‐life is increased after multiple dosing, suggesting an auto‐inhibition of ticlopidine metabolism 12…”