Produção Nacional
Revisado por pares
Pharmacokinetic interactions between clopidogrel and rosuvastatin: Effects on vascular protection in subjects with coronary heart disease
2012; Elsevier BV; Volume: 158; Issue: 1 Linguagem: Inglês
10.1016/j.ijcard.2012.04.051
ISSN1874-1754
AutoresLuiz Pinheiro, Carolina Nunes França, Maria Cristina de Oliveira Izar, Simone P. Barbosa, Henrique Tria Bianco, Soraia H. Kasmas, Gustavo Duarte Mendes, Rui Póvoa, Francisco Antônio Helfenstein Fonseca,
Tópico(s)Acute Myocardial Infarction Research
ResumoSignificant decrease in outcomes with statins administration in the first 24 h of an acute myocardial infarction [1Spencer F.A. Fonarow G.C. Frederick P.D. Wright R.S. Every N. Goldberg R.J. et al.National Registry of Myocardial Infarction. Early withdrawal of statin therapy in patients with non-ST-segment elevation myocardial infarction: national registry of myocardial infarction.Arch Intern Med. 2004; 164: 2162-2168Crossref PubMed Scopus (113) Google Scholar, 2Fonarow G.C. Wright R.S. Spencer F.A. et al.National Registry of Myocardial Infarction 4 Investigators. Effect of statin use within the first 24 hours of admission for acute myocardial infarction on early morbidity and mortality.Am J Cardiol. 2005; 96: 611-616Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar, 3Nagashima M. Koyanagi R. Kasanuki H. Hagiwara N. Yamaguchi J. Atsuchi N. et al.Heart Institute of Japan, Department of Cardiology (HIJC) Investigators. Effect of early statin treatment at standard doses on long-term clinical outcomes in patients with acute myocardial infarction (the Heart Institute of Japan, Department of Cardiology Statin Evaluation Program).Am J Cardiol. 2007; 99: 1523-1528Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 4Wright R.S. Bybee K. Miller W.L. Laudon D.A. Murphy J.G. Jaffe A.S. Reduced risks of death and CHF are associated with statin therapy administered acutely within the first 24 h of AMI.Int J Cardiol. 2006; 108: 314-319Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar] and reduction of myocardial injury markers after high-dose statin given few hours before percutaneous interventions [5Di Sciascio G. Patti G. Pasceri V. Gaspardone A. Colonna G. Montinaro A. Efficacy of atorvastatin reload in patients on chronic statin therapy undergoing percutaneous coronary intervention: results of the ARMYDA-RECAPTURE (Atorvastatin for Reduction of Myocardial Damage During Angioplasty) Randomized Trial.J Am Coll Cardiol. 2009; 54: 558-565Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar, 6Patti G. Cannon C.P. Murphy S.A. et al.Clinical benefit of statin pretreatment in patients undergoing percutaneous coronary intervention: a collaborative patient-level meta-analysis of 13 randomized studies.Circulation. 2011; 123: 1622-1632Crossref PubMed Scopus (150) Google Scholar] were observed. These effects of statins take place before lipid changes [7Di Napoli P. Taccardi A.A. Grilli A. et al.Chronic treatment with rosuvastatin modulates nitric oxide synthase expression and reduces ischemia-reperfusion injury in rat hearts.Cardiovasc Res. 2005; 66: 462-471Crossref PubMed Scopus (93) Google Scholar, 8Zhou Q. Liao J.K. Pleiotropic effects of statins. Basic research and clinical perspectives.Circ J. 2010; 74: 818-826Crossref PubMed Scopus (422) Google Scholar]. Clopidogrel, a pro-drug largely prescribed for patients undergoing stent implantation, is metabolized in the liver via cytochrome P450 (CYP2C19 and CYP3A4) to form an active metabolite that inhibits the P2Y(12) ADP platelet receptor [9Kazui M. Nishiya Y. Ishizuka T. et al.Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite.Drug Metab Dispos. 2010; 38: 92-99Crossref PubMed Scopus (622) Google Scholar, 10Tantry U.S. Kereiakes D.J. Gurbel P.A. Clopidogrel and proton pump inhibitors: influence of pharmacological interactions on clinical outcomes and mechanistic explanations.JACC Cardiovasc Interv. 2011; 4: 365-380Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar]. Rosuvastatin is partially metabolized by CYP2C9 and CYP2C19 [[11]Shitara Y. Sugiyama Y. Pharmacokinetic and pharmacodynamic alterations of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors: drug–drug interactions and interindividual differences in transporter and metabolic enzyme functions.Pharmacol Ther. 2006; 112: 71-105Crossref PubMed Scopus (481) Google Scholar]. Functional and anatomical changes of the endothelium, an inflammatory substrate and coagulation activation participate on the pathophysiology of acute coronary syndromes [12Libby P. Ridker P.M. Hansson G.K. Progress and challenges in translating the biology of atherosclerosis.Nature. 2011; 473: 317-325Crossref PubMed Scopus (2306) Google Scholar, 13Boos C.J. Balakrishnan B. Blann A.D. Lip G.Y. The relationship of circulating endothelial cells to plasma indices of endothelial damage/dysfunction and apoptosis in acute coronary syndromes: implications for prognosis.J Thromb Haemost. 2008; 6: 1841-1850Crossref PubMed Scopus (43) Google Scholar]. New biomarkers, such as endothelial and platelet microparticles (EMP and PMP), endothelial progenitor cells (EPC), platelet function tests and endothelial-dependent flow-mediated dilation (FMD) have been proposed for the evaluation of vascular homeostasis [14Fadini G.P. de Kreutzenberg S. Agostini C. et al.Low CD34+ cell count and metabolic syndrome synergistically increase the risk of adverse outcomes.Atherosclerosis. 2009; 207: 213-219Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, 15da Silva E.F. Fonseca F.A. França C.N. et al.Imbalance between endothelial progenitor cells and microparticles in HIV-infected patients naive for antiretroviral therapy.AIDS. 2011; 25: 1595-1601Crossref PubMed Scopus (38) Google Scholar]. Thus, we examined possible pharmacokinetic interactions between clopidogrel and rosuvastatin, and the consequences on these biomarkers. The protocol was in accordance with the ethical standards of the institution on human experimentation and was approved by the local ethics committee [[16]Coats A.J.S. Shewan L.G. Statement on authorship and publishing ethics in the International Journal of Cardiology.Int J Cardiol. 2011; 153: 257-258https://doi.org/10.1016/j.ijcard.2011.10.119Abstract Full Text Full Text PDF Scopus (192) Google Scholar]. Patients (n=20) aging 49 to 77 years, with stable coronary artery disease were included after having signed a written informed consent. Enrolled subjects were receiving a stable dose of statin for at least 3 months. We excluded patients with baseline LDL-C above 100 mg/dL to prevent possible consequences of statins withdrawal [17Endres M. Laufs U. Discontinuation of statin treatment in stroke patients.Stroke. 2006; 37: 2640-2643Crossref PubMed Scopus (81) Google Scholar, 18Heeschen C. Hamm C.W. Laufs U. et al.Withdrawal of statins increases event rates in patients with acute coronary syndromes.Circulation. 2002; 105: 1446-1452Crossref PubMed Scopus (465) Google Scholar, 19Skrlin S. Hou V. A review of perioperative statin therapy for noncardiac surgery.Semin Cardiothorac Vasc Anesth. 2010; 14: 283-290Crossref PubMed Scopus (16) Google Scholar, 20Puccetti L. Pasqui A.L. Pastorelli M. et al.Platelet hyperactivity after statin treatment discontinuation.Thromb Haemost. 2003; 90: 476-482PubMed Google Scholar], those with uncontrolled metabolic disorders, genetic dyslipidemias, class III/IV heart failure [[21]Hunt S.A. Abraham W.T. Chin M.H. et al.2009 focused update incorporated into the ACC/AHA 2005 Guidelines for the diagnosis and management of heart failure in adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation.Circulation. 2009; 119: e391-e479Crossref PubMed Scopus (1355) Google Scholar], and with intolerance to the study drugs. Prior statin was discontinued for a week in the screening visit, when they were scheduled to baseline visit under use of aspirin 100 mg daily. Fig. 1 summarizes the study design. We evaluated early effects of rosuvastatin and clopidogrel, alone or combined. All drugs were supplied to the patients. Biochemistry and lipid profile analyses were performed in samples obtained after a 12-hour fasting period in a central laboratory of our university by standard techniques. EPCs, EMPs and PMPs were determined by flow cytometry, as previously reported [[15]da Silva E.F. Fonseca F.A. França C.N. et al.Imbalance between endothelial progenitor cells and microparticles in HIV-infected patients naive for antiretroviral therapy.AIDS. 2011; 25: 1595-1601Crossref PubMed Scopus (38) Google Scholar]. Multiple electrode platelet aggregometer (Multiplate 5.0 Analyzer, Diapharma, Diapharma Group Inc., Munich, BV, Germany) tests were performed as reported before [22Breet N.J. van Werkum J.W. Bouman H.J. et al.Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation.JAMA. 2010; 303: 754-762Crossref PubMed Scopus (707) Google Scholar, 23Sibbing D. Braun S. Morath T. et al.Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis.J Am Coll Cardiol. 2009; 53: 849-856Abstract Full Text Full Text PDF PubMed Scopus (569) Google Scholar, 24Eshtehardi P. Windecker S. Cook S. et al.Dual low response to acetylsalicylic acid and clopidogrel is associated with myonecrosis and stent thrombosis after coronary stent implantation.Am Heart J. 2010; 159: 891-898Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar]. Aggregation was induced by collagen (COL), thrombin receptor activating peptide 6 (TRAP-6), adenosine-diphosphate (ADP), and arachidonic acid (ASP), performed in duplicate. For pharmacokinetic studies blood samples were collected at 0, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 10.0, 12.0, 16.0 and 24.0 h post-dosing of the compound of reference. Plasma levels of rosuvastatin and clopidogrel were measured by using validated liquid chromatography with mass spectrometry as previously described [25Nirogi R. Mudigonda K. Kandikere V. Chromatography–mass spectrometry methods for the quantitation of statins in biological samples.J Pharm Biomed Anal. 2007; 44: 379-387Crossref PubMed Scopus (91) Google Scholar, 26França C.N. Pinheiro L.F. Izar M.C. et al.Endothelial progenitor cell mobilization and platelet microparticle release are influenced by clopidogrel plasma levels in stable coronary heart disease.Circ J. 2011 Dec 28; ([Epub ahead of print])PubMed Google Scholar]. FMD of the brachial artery was assessed at each visit by ultrasound (HP 5500) using a high-frequency transducer, as previously reported [[27]Brandão S.A. Izar M.C. Fischer S.M. et al.Early increase in autoantibodies against human oxidized low-density lipoprotein in hypertensive patients after blood pressure control.Am J Hypertens. 2010; 23: 208-214Crossref PubMed Scopus (24) Google Scholar]. Variables were compared between time points using ANOVA-repeated measures followed by Tukey-test or Friedman test, when appropriate. Pharmacokinetic analyses were performed as previously described [[26]França C.N. Pinheiro L.F. Izar M.C. et al.Endothelial progenitor cell mobilization and platelet microparticle release are influenced by clopidogrel plasma levels in stable coronary heart disease.Circ J. 2011 Dec 28; ([Epub ahead of print])PubMed Google Scholar]. Tests were two-tailed and significance was set at a p-value <0.05. Major characteristics of the study participants are shown in Table 1. Fig. 2 shows remarkable changes on LDL-cholesterol levels after statin withdrawal (+61%) and introduction (−39%). We observed lower platelet aggregation to ASP and COL (under aspirin), as well as to ADP tests (under clopidogrel alone or combined with rosuvastatin), whereas responses to TRAP-6 were unchanged (Fig. 3). Improvement in FMD was observed 24-h after rosuvastatin initiation and it was maintained up to last visit (Fig. 4). We observed an interaction with clopidogrel, increasing the AUClast and Cmax of rosuvastatin; however, rosuvastatin did not modify clopidogrel pharmacokinetics (Table 2). There was a trend for higher levels of CD34+/CD133+ subpopulation of EPCs on visit 3. After rosuvastatin withdrawal, an increase in the amount of PMP and a trend for increased levels of EMP were observed (Table 3).Table 1Baseline characteristics of study population.CharacteristicValuesPatients, n (%)20 (100)Age, median (interquartile range)58 (52–64)Sex, n (%) Male14 (74) Female6 (26)Ethnicity, n (%) Caucasian17 (85) Afro descendant3 (15)Weight, kg, mean (SEM)79.2 (3.1)Body mass index, kg/m2, mean (SEM)29.3 (1.0)Systolic blood pressure, mm Hg, mean (SEM)121 (3)Diastolic blood pressure, mm Hg, mean (SEM)75 (2)Medical history, n (%) Prior myocardial infarction15 (75) Unstable angina1 (5) Stable angina3 (15) Coronary artery bypass graft3 (15) Percutaneous coronary intervention13 (65) Hypertension18 (90) Diabetes mellitus6 (30) Active smokers4 (20)Medications, n (%) Statins20 (100) ACEIs/ARBs15 (75) β-blockers15 (75) Calcium channel blockers7 (35) Diuretics8 (40) Aspirin20 (100) Nitrates2 (10) Sulphonylureas/metformin7 (35) Insulin2 (10)Fasting glucose, mg/dL, mean (SEM)104 (4)Creatinine, mg/dL, mean (SEM)0.98 (0.04)CK, IU, mean (SEM)137 (27)ALT, IU, mean (SEM)24 (2)Baseline characteristics of the study population at visit 1. ACEIs=angiotensin-converting enzyme inhibitors; ALT=alanine aminotransferase; ARBs=angiotensin II receptor blockers; CK=creatine phosphokinase. Statins were withdrawn one-week before. Open table in a new tab Fig. 3Box-plots showing platelet aggregation tests by treatment. Visit 1: ASP=aspirin 100 mg; visit 2: R40=rosuvastatin 40 mg; visit 3: R40/CLO75=rosuvastatin 40 mg plus clopidogrel 75 mg; visit 4: CLO75=clopidogrel 75 mg. All samples were obtained with the patients hospitalized immediately before drug administration. ASPtest—activation by arachidonic acid; COLtest—activation by collagen; ADPtest—activation by adenosine diphosphate; TRAPtest—activation by thrombin; AUC=area under the curve in aggregation units. ASPtest: visit 1<visit 2, visit 3, and visit 4 (p<0.0001); COLtest: visit 1 visit 3 and visit 4 (p<0.0001); TRAPtest: unchanged between visits (p=0.53). All analyses were made by ANOVA–Tukey.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig. 4Box-plots showing flow-mediated dilation (FMD) of the brachial artery by treatment. Values were obtained at each visit and 24 h after hospitalization; D=day. D1=aspirin 100 mg; D2=rosuvastatin 40 mg; D8=rosuvastatin 40 mg; D9=rosuvastatin 40 mg+clopidogrel 300 mg; D15=rosuvastatin 40 mg+clopidogrel 75 mg; D16=rosuvastatin 40 mg+clopidogrel 75 mg; D22=clopidogrel 75 mg; D23=clopidogrel 75 mg. FMD at visit 1<FMD 24 h after the initiation of rosuvastatin 40 mg and all FMD dilation obtained in the subsequent visits (p<0.0001, ANOVA–Tukey).View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table 2Pharmacokinetic parameters for clopidogrel and rosuvastatin, by treatment.Visit 1Visit 2Visit 3Visit 4RosuvastatinRosuvastatin+clopidogrelRosuvastatin+clopidogrelclopidogrelRosuvastatin AUClast, ng h/mL178 (25)304 (44)⁎261 (41)⁎NA AUCinf, ng h/mL262 (41)514 (83)368 (54)NA Cmax, ng/mL22.9 (4.2)29.8 (4.3)†24.2 (3.1)NA Tmax, h4.37 (1.23)3.26 (0.31)3.50(031)NA T1/2, h10.77 (1.28)14.98 (1.59)12.78 (1.31)NA Ke, 1/h0.08 (0.01)0.05 (0.00)0.06 (0.01)NAClopidogrel AUClast, ng h/mLNA37 (10)10 (3)10 (2) AUCinf, ng h/mLNA42 (11)13 (3)10 (3) Cmax, ng/mLNA42 (11)3.2 (0.7)3.3 (0.7) Tmax, hNA1.45 (0.19)1.53 (0.31)1.21 (0.19) T1/2, hNA6.27 (0.72)6.02 (1.12)6.37 (1.29) Ke, 1/hNA0.14 (0.02)0.28 (0.07)0.30 (0.09)Visit 1=rosuvastatin 40 mg; visit 2=rosuvastatin 40 mg+clopidogrel 300 mg; visit 3=rosuvastatin 40 mg+clopidogrel 75 mg; visit 4=clopidogrel 75 mg. AUClast=the areas under the clopidogrel and rosuvastatin plasma concentration vs. time curves from 0 to the last detectable concentration; AUCinf=extrapolation of these areas to infinity; Cmax=maximal concentration; Tmax=time to achieve the maximal concentration; T1/2=half-life; Ke=the first-order terminal elimination rate constant; NA=not applicable. ⁎p<0.0001, ANOVA-repeated measures; visit 1<visit 2, p<0.001; visit 1<visit 3, p<0.01, Tukey–Kramer test. †p=0.0114, ANOVA repeated measures; visit 1<visit 2, p<0.05, Tukey–Kramer test. Open table in a new tab Table 3Levels of endothelial progenitor cells and microparticles, by treatment.VariableVisit 1Visit 2Visit 3Visit 4p-ValueAspirinRosuvastatinRosuvastatin+clopidogrelClopidogrelEndothelial progenitor cells, % CD34+/KDR+0.11 (0.04)0.08 (0.05)0.06 (0.02)0.13 (0.04)0.66 CD34+/CD133+0.03 (0.01)0.02 (0.01)0.030 (0.005)0.023 (0.005)0.059 CD133+/KDR+0.06 (0.05)0.003 (0.003)0.02 (0.02)0.003 (0.003)0.54Microparticles, number per μL PPP Endothelial microparticles1498 (489)1397 (543)2975 (790)3737 (932)0.059 Platelet microparticles31,446 (8205)26,050 (5797)37,510 (10,049)74,063 (16,070)0.035Visit 1=rosuvastatin 40 mg; visit 2=rosuvastatin 40 mg+clopidogrel 300 mg; visit 3=rosuvastatin 40 mg+clopidogrel 75 mg; visit 4=clopidogrel 75 mg.Endothelial progenitor cells are expressed as % of the lymphocyte gate; microparticles as counts per μL of poor platelet plasma (PPP). Comparisons between treatments were made by the Friedman test. Open table in a new tab Baseline characteristics of the study population at visit 1. ACEIs=angiotensin-converting enzyme inhibitors; ALT=alanine aminotransferase; ARBs=angiotensin II receptor blockers; CK=creatine phosphokinase. Statins were withdrawn one-week before. Visit 1=rosuvastatin 40 mg; visit 2=rosuvastatin 40 mg+clopidogrel 300 mg; visit 3=rosuvastatin 40 mg+clopidogrel 75 mg; visit 4=clopidogrel 75 mg. AUClast=the areas under the clopidogrel and rosuvastatin plasma concentration vs. time curves from 0 to the last detectable concentration; AUCinf=extrapolation of these areas to infinity; Cmax=maximal concentration; Tmax=time to achieve the maximal concentration; T1/2=half-life; Ke=the first-order terminal elimination rate constant; NA=not applicable. ⁎p<0.0001, ANOVA-repeated measures; visit 1<visit 2, p<0.001; visit 1<visit 3, p<0.01, Tukey–Kramer test. †p=0.0114, ANOVA repeated measures; visit 1<visit 2, p<0.05, Tukey–Kramer test. Visit 1=rosuvastatin 40 mg; visit 2=rosuvastatin 40 mg+clopidogrel 300 mg; visit 3=rosuvastatin 40 mg+clopidogrel 75 mg; visit 4=clopidogrel 75 mg. Endothelial progenitor cells are expressed as % of the lymphocyte gate; microparticles as counts per μL of poor platelet plasma (PPP). Comparisons between treatments were made by the Friedman test. Our study reports interaction between clopidogrel and rosuvastatin, increasing rosuvastatin concentrations. As rosuvastatin is active independently of its metabolization [[28]Bailey K.M. Romaine S.P. Jackson B.M. et al.SPACE ROCKET Trial Group. Hepatic metabolism and transporter gene variants enhance response to rosuvastatin in patients with acute myocardial infarction: the GEOSTAT-1 Study.Circ Cardiovasc Genet. 2010; 3: 276-285Crossref PubMed Scopus (83) Google Scholar], concomitant clopidogrel therapy does not reduce its benefits, as per the early and sustained lipid changes, and the impressive improvement in FMD 24-h after statin initiation. Abrupt statin withdrawal leads to an overshoot activation of HMG-CoA reductase, Rho and Rac with loss of the pleiotropic effects [[29]Endres M. Laufs U. Effects of statins on endothelium and signaling mechanisms.Stroke. 2004; 35: 2708-2711Crossref PubMed Scopus (147) Google Scholar]. Rosuvastatin seems to act synergistically with clopidogrel. Riondino et al. [[30]Riondino S. Petrini N. Donato L. et al.Effects of rosuvastatin on platelet inhibition by clopidogrel in cardiovascular patients.J Thromb Thrombolysis. 2009; 28: 151-155Crossref PubMed Scopus (18) Google Scholar] demonstrated neutral effects of rosuvastatin on platelet inhibition by clopidogrel. Our study showed, dynamically, the effects of rosuvastatin and clopidogrel introduction/withdrawal not only on platelet function, but also on EPCs mobilization and MPs release. In fact, rosuvastatin withdrawal increased the amount of PMP, suggesting augmented platelet consumption or apoptosis [31Vasina E.M. Cauwenberghs S. Feijge M.A. Heemskerk J.W. Weber C. Koenen R.R. Microparticles from apoptotic platelets promote resident macrophage differentiation.Cell Death Dis. 2011; 2: e210Crossref PubMed Scopus (99) Google Scholar, 32Rautou P.E. Vion A.C. Amabile N. et al.Microparticles, vascular function, and atherothrombosis.Circ Res. 2011; 109: 593-606Crossref PubMed Scopus (280) Google Scholar]. The observed trend for lower percentages of EPCs and higher levels of EMPs 1 week after rosuvastatin withdrawal, seems to imply the importance of the maintenance of combined therapy for a more comprehensive cardiovascular protection. Interestingly, the interaction between clopidogrel on plasma levels of rosuvastatin occurred exclusively after the loading dose (300 mg) and not with the 75 mg dose. On this view, some pleiotropic effects of statins in the first 24-h of myocardial infarction appear to play an important role in the early cardiovascular outcomes, and can be due to recovery of ischemic tissue in areas surrounding the necrotic core, probably due to the improvement of the microcirculation [33Tang X.L. Sanganalmath S.K. Sato H. et al.Atorvastatin therapy during the peri-infarct period attenuates left ventricular dysfunction and remodeling after myocardial infarction.PLoS One. 2011; 6: e25320Crossref PubMed Scopus (20) Google Scholar, 34Ye Y. Perez-Polo J.R. Birnbaum Y. Protecting against ischemia-reperfusion injury: antiplatelet drugs, statins, and their potential interactions.Ann N Y Acad Sci. 2010; 1207: 76-82Crossref PubMed Scopus (24) Google Scholar]. Most of the absorbed clopidogrel (∼85%) is hydrolyzed by hepatic carboxylesterase to an inactive carboxylic acid metabolite, and the remaining ∼15% is converted to an active thiol metabolite in a 2-step process [9Kazui M. Nishiya Y. Ishizuka T. et al.Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite.Drug Metab Dispos. 2010; 38: 92-99Crossref PubMed Scopus (622) Google Scholar, 10Tantry U.S. Kereiakes D.J. Gurbel P.A. Clopidogrel and proton pump inhibitors: influence of pharmacological interactions on clinical outcomes and mechanistic explanations.JACC Cardiovasc Interv. 2011; 4: 365-380Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar]. CYP2C19, CYP1A2, and CYP2B6 isoenzymes are responsible for the first step, whereas CYP2C19, CYP2C9, CYP2B6, and CYP3A4 are responsible for the second step [[9]Kazui M. Nishiya Y. Ishizuka T. et al.Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite.Drug Metab Dispos. 2010; 38: 92-99Crossref PubMed Scopus (622) Google Scholar]. The extrapolation of our findings to statins that are pro-drugs seems premature. In addition, liver metabolization by other isoenzymes may produce other interactions and lack of synergistic effects with clopidogrel [35Zahno A. Brecht K. Bodmer M. Bur D. Tsakiris D.A. Krähenbühl S. Effects of drug interactions on biotransformation and antiplatelet effect of clopidogrel in vitro.Br J Pharmacol. 2010; 161: 393-404Crossref PubMed Scopus (40) Google Scholar, 36Farid N.A. Small D.S. Payne C.D. et al.Effect of atorvastatin on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel in healthy subjects.Pharmacotherapy. 2008; 28: 1483-11494Crossref PubMed Scopus (84) Google Scholar]. It is possible that changes in the amount of MPs and EPCs are more pronounced among statin naïve patients. We suggest a beneficial synergism between clopidogrel and rosuvastatin, determining a broader cardiovascular protection than that provided by each drug alone. This study was funded by the Sao Paulo State Foundation (FAPESP), grant # 2008/54459-6 and in part from a grant support from the National Institute of Complex Fluids , Institute of Physics, University of São Paulo, São Paulo, SP, Brazil. Dr. Pinheiro was recipient of a research grant from the National Council of Research Foundation (CNPq). The authors of this article have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [[16]Coats A.J.S. Shewan L.G. Statement on authorship and publishing ethics in the International Journal of Cardiology.Int J Cardiol. 2011; 153: 257-258https://doi.org/10.1016/j.ijcard.2011.10.119Abstract Full Text Full Text PDF Scopus (192) Google Scholar].
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