To investigate relations between pharmacokinetics (PK) and pharmacodynamics (PD) of clopidogrel active metabolite (CAM) we studied 14 patients undergoing elective percutaneous coronary intervention for unstable angina or NSTE acute coronary syndrome. Plasma concentrations of clopidogrel and CAM (UHPLC-MS/MS), phosphorylation of vasodilator stimulated phosphoprotein (VASP) expressed in platelet reactivity index (PRI) and platelet aggregation in whole blood (Multiplate) were measured in blood samples collected before and after (0.5, 1, 1.5, 2, 3, 4, 8, 24h) 600 mg clopidogrel, and before and 4h after 75 mg, at days 2, 7 and 30. The plasma concentrations of clopidogrel and CAM were highly variable. CAM reached maximal concentration (Cmax) (median: 55.9 nmol/L; range: 21.2-244.8) 0.5-1.5h after the administration of 600mg clopidogrel. CAM PK dissociate from its PD, because inhibition of PRI and maximal aggregation increased progressively up to 24h, when CAM was undetectable in 12 patients. CAM Cmax significantly correlated with PRI at each time point from 1h to 24h, when the strongest correlation was observed (r=0.922, P<0.0001). CAM Cmax also predicted PRI values at days 2, 7 and 30, both before and 4h after dosing (day 30: r=0.87, P<0.001, n=10). In seven patients with the lowest CAM Cmax (<40 nmol/L), PRI was unchanged from baseline, indicating low sensitivity of the test. The relation between CAM Cmax values and PRI was defined by a sigmoid curve, which paralleled the curve obtained when different concentrations of CAM were added in vitro to normal blood. Platelet aggregation measured by Multiplate did not show significant correlation with PRI or CAM Cmax at any time point. The results of the present study indicate that after the administration of 600mg clopidogrel changes in VASP phosphorylation are almost entirely explained by maximal CAM concentration. This finding may help define relations between CAM bioavailability, platelet function and clinical events.
Pharmacokinetics of clopidogrel: the active metabolite is the major determinat of VASP phosphorylation in patients with coronary artery disease
DANESE, Elisa;FAVA, Cristiano;CALABRIA, Stefano;BENATI, Marco;GIACOMAZZI, Alice;GOTTARDO, Rossella;TAGLIARO, Franco;GUIDI, Giancesare;MINUZ, Pietro
2014-01-01
Abstract
To investigate relations between pharmacokinetics (PK) and pharmacodynamics (PD) of clopidogrel active metabolite (CAM) we studied 14 patients undergoing elective percutaneous coronary intervention for unstable angina or NSTE acute coronary syndrome. Plasma concentrations of clopidogrel and CAM (UHPLC-MS/MS), phosphorylation of vasodilator stimulated phosphoprotein (VASP) expressed in platelet reactivity index (PRI) and platelet aggregation in whole blood (Multiplate) were measured in blood samples collected before and after (0.5, 1, 1.5, 2, 3, 4, 8, 24h) 600 mg clopidogrel, and before and 4h after 75 mg, at days 2, 7 and 30. The plasma concentrations of clopidogrel and CAM were highly variable. CAM reached maximal concentration (Cmax) (median: 55.9 nmol/L; range: 21.2-244.8) 0.5-1.5h after the administration of 600mg clopidogrel. CAM PK dissociate from its PD, because inhibition of PRI and maximal aggregation increased progressively up to 24h, when CAM was undetectable in 12 patients. CAM Cmax significantly correlated with PRI at each time point from 1h to 24h, when the strongest correlation was observed (r=0.922, P<0.0001). CAM Cmax also predicted PRI values at days 2, 7 and 30, both before and 4h after dosing (day 30: r=0.87, P<0.001, n=10). In seven patients with the lowest CAM Cmax (<40 nmol/L), PRI was unchanged from baseline, indicating low sensitivity of the test. The relation between CAM Cmax values and PRI was defined by a sigmoid curve, which paralleled the curve obtained when different concentrations of CAM were added in vitro to normal blood. Platelet aggregation measured by Multiplate did not show significant correlation with PRI or CAM Cmax at any time point. The results of the present study indicate that after the administration of 600mg clopidogrel changes in VASP phosphorylation are almost entirely explained by maximal CAM concentration. This finding may help define relations between CAM bioavailability, platelet function and clinical events.
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