Pharmacokinetics of ticlopidine during chronic oral administration to healthy volunteers and its effects on antipyrine pharmacokinetics

Abstract

1. The pharmacokinetics of ticlopidine, a novel antithrombotic agent, have been investigated in 10 healthy volunteers dosed orally with the drug (250 mg 12 hourly for 21 days), to determine the basic pharmacokinetic parameters in humans, to investigate its accumulation during repeated administration, and to assess its effects on hepatic drug-metabolizing enzymes. 2. After the first dose, peak plasma concentrations (median 0.31, range 0.08-0.80 mg/l) were generally found at 2 h. The levels decreased rapidly to a median concentration of 0.087 mg/l by 4 h then declined to 0.022 (range less than 0.005-0.128) mg/l at 12 h after administration, with apparent half-lives of approx. 4 h. The median AUC value for this first dosage interval (AUC tau) was 0.97 (range 0.41-3.49) mg h l-1. 3. Pre-dose plasma concentrations indicated that steady state was reached after 5-10 days, and then remained essentially unchanged through to the end of the study. From 30 h after the final dose, drug levels declined exponentially with a median half-life of 28.8 (range less than or equal to 20-50) h. 4. Following the final dose, the median peak concentration and AUC tau were 0.99 (range 0.22-2.12) mg/l and 4.06 (range 0.90-15.2) mg h l-1 respectively. Based on AUC values, the mean accumulation factor +/- SD was 3.73 +/- 1.14. 5. The metabolic status of subjects was assessed by administration of single doses of antipyrine (700 mg orally) 7 days before the first dose of ticlopidine and 2 days after the final dose. Treatment with ticlopidine decreased antipyrine clearance, demonstrating that it inhibited drug-metabolizing enzymes. Significant correlations (r2 = 0.84, p less than 0.01) were found between the AUC values for ticlopidine and antipyrine, indicating that the interindividual variation in the pharmacokinetics of ticlopidine are explained by differences in metabolic clearance.

Determination of ticlopidine in human plasma by capillary gas chromatography with ion trap detection

“…6). The time taken to achieve the maximal plasma concentration was approximately 2 h and it is in agreement with others studies [13,15,16].…”

Determination of Ticlopidine in Pharmaceutical Tablets by Flow Injection Analysis Using UV-Detection

“…[9,10] A limited number of analytical techniques have been used for the determination of TP in drugs and biological samples. TP concentrations were determined by liquid chromatography [11][12][13][14][15][16][17][18] and gas chromatography [19][20][21] coupled with different types of detectors in these studies. The proposed method in the European Pharmacopoeia [22] is also a gas chromatographic method with flame-ionization detection.…”

Ticlopidine quantification in human plasma by high‐performance liquid chromatography coupled to electrospray tandem mass spectrometry. Application to bioequivalence study

“…Ticlopidine has been determined in plasma and other biological fluids by using HPLC coupled to spectrophometric detection, 6 HPLC coupled to gas chromatography (GC)/MS, 7 GC with thermoionic detection, 8 GC with nitrogen-phosphorus detection (GC/NPD), 9,10 GC/MS, 7,9 HPLC coupled to UV detection 11 -15 and LC coupled with positive ion electrospray MS (LC/(C)ES-MS). 16 This is the first reported study of plasma measurement of ticlopidine using HPLC/MS/MS.…”