Pharmacokinetics of clopidogrel

Area of Science:

• Pharmacology
• Drug Metabolism
• Clinical Pharmacokinetics

Background:

• Clopidogrel undergoes extensive metabolism, with minimal unchanged drug detected in plasma.
• The inactive carboxylic acid metabolite, SR26334, is the major circulating compound.
• Understanding the pharmacokinetics of SR26334 is crucial for assessing clopidogrel absorption and elimination.

Purpose of the Study:

• To investigate the single-dose pharmacokinetics of SR26334 following oral clopidogrel administration.
• To evaluate the dose-proportionality of SR26334 pharmacokinetics across a range of clopidogrel doses.
• To assess the multiple-dose pharmacokinetics of SR26334 during short-term and long-term clopidogrel treatment.

Main Methods:

• A randomized, dose-proportionality study involving single oral doses of clopidogrel (50, 75, 100, 150 mg) in 12 healthy male volunteers.
• Multiple-dose pharmacokinetic studies in 18 subjects (75 mg daily for 14 days) and 35 subjects (75 mg daily for 12 weeks).
• Analysis of SR26334 plasma concentrations (Cmax, Tmax, t1/2, C(trough)) and urinary excretion.

Main Results:

• SR26334 Cmax demonstrated a dose-proportional increase with clopidogrel doses from 50 to 150 mg.
• Urinary excretion of SR26334 was low (2.2-2.4%), with constant renal clearance (Cl(r-2-24)).
• Median Tmax and mean plasma t1/2 of SR26334 were consistent across doses, and steady-state trough concentrations were reproducible during long-term treatment.

Conclusions:

• Clopidogrel absorption and elimination, as reflected by SR26334 pharmacokinetics, are dose-proportional within the studied range.
• The esterasic biotransformation of clopidogrel to its carboxylic acid metabolite remains consistent over several months of treatment.
• These findings support the predictable pharmacokinetic profile of clopidogrel's major metabolite during therapy.