Ticlopidine

Abstract

Ticlopidine is an antiplatelet drug which inhibits the adenosine diphosphate (ADP) receptor on platelets, and thereby reduces platelet activation and aggregration, and subsequent serious vascular events in patients at risk of thrombotic events. ChemistryThe chemical name of ticlopidine hydrochloride is 5-[(2-Chlorophenyl)-methyl]-4,5,6,7-tetrahydrothieno [3,2-c] pyridinehydrochloride.The empirical formula of ticlopidine hydrochloride is C 14 H 14 ClNS-HCl ( Figure 1).Ticlopidine is a thienopyridine derivative and has a thienopyridine ring in its structure. It has a molecular weight of 300.25 daltons. It is a white crystalline powder which is freely soluble in water and methanol.It is sparingly soluble in methylene chloride, ethanol and buffer solutions above pH 6.0 and slightly soluble in acetone. An aqueous solution of ticlopidine has a pH of 3.6. Pharmacokinetic propertiesAbsorption Approximately 80-90% of an oral dose of ticlopidine is absorbed in healthy volunteers 1 . Absorption of ticlopidine is improved when the drug is administered with food 2 . Plasma concentrationsSingle dose A single 250 mg dose of ticlopidine produces a peak plasma concentration (Cmax) of between 0.31 and 0.70 mg/L at 1.7-2.0 h after administration in healthy volunteers 3-5 . Administration of a single 250 mg dose of [ 14 C]-ticlopidine in untreated subjects realises only 5% of the area under the plasma concentration-time curve (AUC) for plasma radioactivity during the first 8 h after administration. Repeated dosesRepeated doses of 250 mg bid of ticlopidine given to healthy volunteers produces steady-state plasma concentrations after 5-14 days, and values for Cmax of 0.89-1.42 mg/L 5,6 . After multiple dosing with nonlabeled ticlopidine, the proportion of ticlopidine to total radioactivity in plasma increases to approximately 15% of plasma radioactivity over 8 h 4 . The increase in ticlopidine concentrations and the increased proportion of total radioactivity after multiple dosing suggests that metabolism of ticlopidine is saturated after chronic dosing. This finding is consistent with multiple-dose pharmacokinetic studies of ticlopidine 5 . Influence of food and antacidAdministration of a single 250 mg dose of ticlopidine together with food results in 11% less time to reach Cmax, and the values for Cmax and AUC are 20% higher, compared with administration of ticlopidine after fasting 7 . Administration of ticlopidine with food is recommended to maximize gastrointestinal tolerance.In contrast, administration of ticlopidine with an antacid results in a significant decrease in AUC but no change in the rate of absorption, compared with adminstration after fasting 7 .