CYP2C19*17 increases clopidogrel‐mediated platelet inhibition but does not alter the pharmacokinetics of the active metabolite of clopidogrel

Abstract

The aim of the present study was to determine the impact of CYP2C19*17 on the pharmacokinetics and pharmacodynamics of the active metabolite of clopidogrel and the pharmacokinetics of proguanil. Thus, we conducted an open-label two-phase cross-over study in 31 healthy male volunteers (11 CYP2C19*1/*1, 11 CYP2C19*1/*17 and nine CYP2C19*17/*17). In Phase A, the pharmacokinetics of the derivatized active metabolite of clopidogrel (CAMD) and platelet function were determined after administration of a single oral dose of 600 mg clopidogrel (Plavix; Sanofi-Avensis, Horsholm, Denmark). In Phase B, the pharmacokinetics of proguanil and its metabolites cycloguanil and 4-chlorphenylbiguanide (4-CPB) were determined in 29 of 31 subjects after a single oral dose of 200 mg proguanil given as the combination drug Malarone (GlaxoSmithKline Pharma, Brondby, Denmark). Significant correlations were found between the area under the time-concentration curve (AUC0-∞ ) of CAMD and both the absolute ADP-induced P2Y12 receptor-activated platelet aggregation (r = -0.60, P = 0.0007) and the percentage inhibition of aggregation (r = 0.59, P = 0.0009). In addition, the CYP2C19*17/*17 and CYP2C19*1/*17 genotype groups had significantly higher percentage inhibition of platelet aggregation compared with the CYP2C19*1/*1 subjects (geometric mean percentage inhibition of 84%, 73% and 63%, respectively; P = 0.014). Neither the absolute ADP-induced P2Y12 receptor-activated platelet aggregation, exposure to CAMD nor the pharmacokinetic parameters of proguanil, cycloguanil and 4-CPB exhibited any significant differences among the genotype groups. In conclusion, carriers of CYP2C19*17 exhibit higher percentage inhibition of platelet aggregation, but do not have significantly lower absolute P2Y12 receptor-activated platelet aggregation or higher exposure to the active metabolite after a single oral administration of 600 mg clopidogrel.

OCT1 Deficiency Affects Hepatocellular Concentrations and Pharmacokinetics of Cycloguanil, the Active Metabolite of the Antimalarial Drug Proguanil

“…[12][13][14][15][16] The CYP2C19 variant *17 is associated with increased CYP2C19 activity, 17 but may not significantly affect proguanil or cycloguanil pharmacokinetics. 18 A smaller fraction of cycloguanil is also formed by CYP3A enzymes 4 and/or 5. [19][20][21] However, genetic polymorphisms in CYP2C19 and CYP3A did not, or only partially, explain treatment failures or adverse events of proguanil.…”

“…Due to the heritable variants CYP2C19*2 and *3 about 3% of white and African American people and about 15% of Asian people are poor CYP2C19 metabolizers and have much lower cycloguanil blood concentrations . The CYP2C19 variant *17 is associated with increased CYP2C19 activity, but may not significantly affect proguanil or cycloguanil pharmacokinetics . A smaller fraction of cycloguanil is also formed by CYP3A enzymes 4 and/or 5 .…”

CYP2C19⁎2 Polymorphism in Chilean Patients with In-Stent Restenosis Development and Controls

“…CYP2C19 ∗ 2 corresponds to a change of guanine by adenine at position 681 in exon 5 and results in a loss-of-function allele associated with decreased conversion of clopidogrel to its active metabolite, increased platelet reactivity during therapy, and poor clinical outcome, with a potential increase of in-stent thrombosis [6, 10]. On the contrary, the CYP2C19 ∗ 17 variant is associated with increased antiplatelet therapeutic response and a better clinical outcome [11–13]. Additionally, reports show that clopidogrel can prevent restenosis occurrence, partly due to the fact that inhibition of platelet activity would in turn decrease the release of platelet-derived growth factor (PDGF) [14, 15], which is a potent stimulator of vascular smooth muscle cell (VSMC) proliferation and cell migration [16].…”

Pharmacogenetics of drug oxidation via cytochrome P450 (CYP) in the populations of Denmark, Faroe Islands and Greenland

“…Fluvoxamine is also a potent inhibitor of the cycloguanil formation in vitro [108] ; both studies confirmed that the cycloguanil formation is heavily dependent on CYP2C19, and they further showed that fluvoxamine is a potent inhibitor of CYP2C19. Very recently, we have studied the single oral dose pharmacokinetics of 200 mg of proguanil in 11 Danish CYP2C19 * 1/ * 1 , 11 CYP2C19 * 1/ * 17 and 9 CYP2C19 * 17/ * 17 [109] , but somewhat surprisingly, the formation of cycloguanil was not enhanced in carriers of the * 17 mutation.…”

“…Thirty-one healthy, male subjects took a single oral dose of 600 mg clopidogrel [109] . There were 11 CYP2C19 * 1/CYP2C19 * 1 , 11 CYP2C19 * 1/CYP2C19 * 17 and 9 CYP2C19 * 17/CYP2C19 * 17 [27] .…”