The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Kristian Linnet - One of the best experts on this subject based on the ideXlab platform.
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in vitro drug metabolism by human carboxylesterase 1 focus on angiotensin converting Enzyme Inhibitors
Drug Metabolism and Disposition, 2014Co-Authors: Ragnar Thomsen, Henrik B Rasmussen, Kristian LinnetAbstract:Carboxylesterase 1 (CES1) is the major hydrolase in human liver. The Enzyme is involved in the metabolism of several important therapeutic agents, drugs of abuse, and endogenous compounds. However, no studies have described the role of human CES1 in the activation of two commonly prescribed angiotensin-converting Enzyme Inhibitors: enalapril and ramipril. Here, we studied recombinant human CES1- and CES2-mediated hydrolytic activation of the prodrug esters enalapril and ramipril, compared with the activation of the known substrate trandolapril. Enalapril, ramipril, and trandolapril were readily hydrolyzed by CES1, but not by CES2. Ramipril and trandolapril exhibited Michaelis-Menten kinetics, while enalapril demonstrated substrate inhibition kinetics. Intrinsic clearances were 1.061, 0.360, and 0.02 ml/min/mg protein for ramipril, trandolapril, and enalapril, respectively. Additionally, we screened a panel of therapeutic drugs and drugs of abuse to assess their inhibition of the hydrolysis of p -nitrophenyl acetate by recombinant CES1 and human liver microsomes. The screening assay confirmed several known Inhibitors of CES1 and identified two previously unreported Inhibitors: the dihydropyridine calcium antagonist, isradipine, and the immunosuppressive agent, tacrolimus. CES1 plays a role in the metabolism of several drugs used in the treatment of common conditions, including hypertension, congestive heart failure, and diabetes mellitus; thus, there is a potential for clinically relevant drug-drug interactions. The findings in the present study may contribute to the prediction of such interactions in humans, thus opening up possibilities for safer drug treatments.
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in vitro drug metabolism by human carboxylesterase 1 focus on angiotensin converting Enzyme Inhibitors
Drug Metabolism and Disposition, 2014Co-Authors: Ragnar Thomsen, Henrik B Rasmussen, Kristian LinnetAbstract:Carboxylesterase 1 (CES1) is the major hydrolase in human liver. The Enzyme is involved in the metabolism of several important therapeutic agents, drugs of abuse, and endogenous compounds. However, no studies have described the role of human CES1 in the activation of two commonly prescribed angiotensin-converting Enzyme Inhibitors: enalapril and ramipril. Here, we studied recombinant human CES1- and CES2-mediated hydrolytic activation of the prodrug esters enalapril and ramipril, compared with the activation of the known substrate trandolapril. Enalapril, ramipril, and trandolapril were readily hydrolyzed by CES1, but not by CES2. Ramipril and trandolapril exhibited Michaelis-Menten kinetics, while enalapril demonstrated substrate inhibition kinetics. Intrinsic clearances were 1.061, 0.360, and 0.02 ml/min/mg protein for ramipril, trandolapril, and enalapril, respectively. Additionally, we screened a panel of therapeutic drugs and drugs of abuse to assess their inhibition of the hydrolysis of p-nitrophenyl acetate by recombinant CES1 and human liver microsomes. The screening assay confirmed several known Inhibitors of CES1 and identified two previously unreported Inhibitors: the dihydropyridine calcium antagonist, isradipine, and the immunosuppressive agent, tacrolimus. CES1 plays a role in the metabolism of several drugs used in the treatment of common conditions, including hypertension, congestive heart failure, and diabetes mellitus; thus, there is a potential for clinically relevant drug-drug interactions. The findings in the present study may contribute to the prediction of such interactions in humans, thus opening up possibilities for safer drug treatments.
Henrik B Rasmussen - One of the best experts on this subject based on the ideXlab platform.
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clopidogrel bioactivation and risk of bleeding in patients cotreated with angiotensin converting Enzyme Inhibitors after myocardial infarction a proof of concept study
Clinical Pharmacology & Therapeutics, 2014Co-Authors: Karl Emil Kristensen, Henrik B Rasmussen, Hao Jie Zhu, Xinwen Wang, Gunnar H Gislason, Christian Torppedersen, John S Markowitz, Peter Riis HansenAbstract:Clopidogrel is an oral antiplatelet prodrug, the majority of which is hydrolyzed to an inactive metabolite by hepatic carboxylesterase 1 (CES1). Most angiotensin-converting Enzyme Inhibitors (ACEIs) are also metabolized by this Enzyme. We examined the effects of ACEIs on clopidogrel bioactivation in vitro and linked the results with a pharmacoepidemiological study. In vitro, ACEIs inhibited CES1-mediated hydrolysis of a model substrate, and trandolapril and enalapril increased formation of clopidogrel active metabolite. In 70,934 patients with myocardial infarction, hazard ratios for clinically significant bleeding in ACEI-treated patients cotreated with or without clopidogrel were 1.10 (95% confidence interval (CI): 0.97–1.25, P = 0.124) and 0.90 (95% CI: 0.81–0.99, P = 0.025), respectively, as compared with patients who did not receive ACEIs. This difference was statistically significant (P = 0.002). We conclude that cotreatment with selected ACEIs and clopidogrel may increase the risk of bleeding. Combination of in vitro and pharmacoepidemiological studies may be a useful paradigm for assessment of drug–drug interactions. Clinical Pharmacology & Therapeutics (2014); 96 6, 713–722. doi:10.1038/clpt.2014.183
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in vitro drug metabolism by human carboxylesterase 1 focus on angiotensin converting Enzyme Inhibitors
Drug Metabolism and Disposition, 2014Co-Authors: Ragnar Thomsen, Henrik B Rasmussen, Kristian LinnetAbstract:Carboxylesterase 1 (CES1) is the major hydrolase in human liver. The Enzyme is involved in the metabolism of several important therapeutic agents, drugs of abuse, and endogenous compounds. However, no studies have described the role of human CES1 in the activation of two commonly prescribed angiotensin-converting Enzyme Inhibitors: enalapril and ramipril. Here, we studied recombinant human CES1- and CES2-mediated hydrolytic activation of the prodrug esters enalapril and ramipril, compared with the activation of the known substrate trandolapril. Enalapril, ramipril, and trandolapril were readily hydrolyzed by CES1, but not by CES2. Ramipril and trandolapril exhibited Michaelis-Menten kinetics, while enalapril demonstrated substrate inhibition kinetics. Intrinsic clearances were 1.061, 0.360, and 0.02 ml/min/mg protein for ramipril, trandolapril, and enalapril, respectively. Additionally, we screened a panel of therapeutic drugs and drugs of abuse to assess their inhibition of the hydrolysis of p -nitrophenyl acetate by recombinant CES1 and human liver microsomes. The screening assay confirmed several known Inhibitors of CES1 and identified two previously unreported Inhibitors: the dihydropyridine calcium antagonist, isradipine, and the immunosuppressive agent, tacrolimus. CES1 plays a role in the metabolism of several drugs used in the treatment of common conditions, including hypertension, congestive heart failure, and diabetes mellitus; thus, there is a potential for clinically relevant drug-drug interactions. The findings in the present study may contribute to the prediction of such interactions in humans, thus opening up possibilities for safer drug treatments.
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in vitro drug metabolism by human carboxylesterase 1 focus on angiotensin converting Enzyme Inhibitors
Drug Metabolism and Disposition, 2014Co-Authors: Ragnar Thomsen, Henrik B Rasmussen, Kristian LinnetAbstract:Carboxylesterase 1 (CES1) is the major hydrolase in human liver. The Enzyme is involved in the metabolism of several important therapeutic agents, drugs of abuse, and endogenous compounds. However, no studies have described the role of human CES1 in the activation of two commonly prescribed angiotensin-converting Enzyme Inhibitors: enalapril and ramipril. Here, we studied recombinant human CES1- and CES2-mediated hydrolytic activation of the prodrug esters enalapril and ramipril, compared with the activation of the known substrate trandolapril. Enalapril, ramipril, and trandolapril were readily hydrolyzed by CES1, but not by CES2. Ramipril and trandolapril exhibited Michaelis-Menten kinetics, while enalapril demonstrated substrate inhibition kinetics. Intrinsic clearances were 1.061, 0.360, and 0.02 ml/min/mg protein for ramipril, trandolapril, and enalapril, respectively. Additionally, we screened a panel of therapeutic drugs and drugs of abuse to assess their inhibition of the hydrolysis of p-nitrophenyl acetate by recombinant CES1 and human liver microsomes. The screening assay confirmed several known Inhibitors of CES1 and identified two previously unreported Inhibitors: the dihydropyridine calcium antagonist, isradipine, and the immunosuppressive agent, tacrolimus. CES1 plays a role in the metabolism of several drugs used in the treatment of common conditions, including hypertension, congestive heart failure, and diabetes mellitus; thus, there is a potential for clinically relevant drug-drug interactions. The findings in the present study may contribute to the prediction of such interactions in humans, thus opening up possibilities for safer drug treatments.
Ragnar Thomsen - One of the best experts on this subject based on the ideXlab platform.
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in vitro drug metabolism by human carboxylesterase 1 focus on angiotensin converting Enzyme Inhibitors
Drug Metabolism and Disposition, 2014Co-Authors: Ragnar Thomsen, Henrik B Rasmussen, Kristian LinnetAbstract:Carboxylesterase 1 (CES1) is the major hydrolase in human liver. The Enzyme is involved in the metabolism of several important therapeutic agents, drugs of abuse, and endogenous compounds. However, no studies have described the role of human CES1 in the activation of two commonly prescribed angiotensin-converting Enzyme Inhibitors: enalapril and ramipril. Here, we studied recombinant human CES1- and CES2-mediated hydrolytic activation of the prodrug esters enalapril and ramipril, compared with the activation of the known substrate trandolapril. Enalapril, ramipril, and trandolapril were readily hydrolyzed by CES1, but not by CES2. Ramipril and trandolapril exhibited Michaelis-Menten kinetics, while enalapril demonstrated substrate inhibition kinetics. Intrinsic clearances were 1.061, 0.360, and 0.02 ml/min/mg protein for ramipril, trandolapril, and enalapril, respectively. Additionally, we screened a panel of therapeutic drugs and drugs of abuse to assess their inhibition of the hydrolysis of p -nitrophenyl acetate by recombinant CES1 and human liver microsomes. The screening assay confirmed several known Inhibitors of CES1 and identified two previously unreported Inhibitors: the dihydropyridine calcium antagonist, isradipine, and the immunosuppressive agent, tacrolimus. CES1 plays a role in the metabolism of several drugs used in the treatment of common conditions, including hypertension, congestive heart failure, and diabetes mellitus; thus, there is a potential for clinically relevant drug-drug interactions. The findings in the present study may contribute to the prediction of such interactions in humans, thus opening up possibilities for safer drug treatments.
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in vitro drug metabolism by human carboxylesterase 1 focus on angiotensin converting Enzyme Inhibitors
Drug Metabolism and Disposition, 2014Co-Authors: Ragnar Thomsen, Henrik B Rasmussen, Kristian LinnetAbstract:Carboxylesterase 1 (CES1) is the major hydrolase in human liver. The Enzyme is involved in the metabolism of several important therapeutic agents, drugs of abuse, and endogenous compounds. However, no studies have described the role of human CES1 in the activation of two commonly prescribed angiotensin-converting Enzyme Inhibitors: enalapril and ramipril. Here, we studied recombinant human CES1- and CES2-mediated hydrolytic activation of the prodrug esters enalapril and ramipril, compared with the activation of the known substrate trandolapril. Enalapril, ramipril, and trandolapril were readily hydrolyzed by CES1, but not by CES2. Ramipril and trandolapril exhibited Michaelis-Menten kinetics, while enalapril demonstrated substrate inhibition kinetics. Intrinsic clearances were 1.061, 0.360, and 0.02 ml/min/mg protein for ramipril, trandolapril, and enalapril, respectively. Additionally, we screened a panel of therapeutic drugs and drugs of abuse to assess their inhibition of the hydrolysis of p-nitrophenyl acetate by recombinant CES1 and human liver microsomes. The screening assay confirmed several known Inhibitors of CES1 and identified two previously unreported Inhibitors: the dihydropyridine calcium antagonist, isradipine, and the immunosuppressive agent, tacrolimus. CES1 plays a role in the metabolism of several drugs used in the treatment of common conditions, including hypertension, congestive heart failure, and diabetes mellitus; thus, there is a potential for clinically relevant drug-drug interactions. The findings in the present study may contribute to the prediction of such interactions in humans, thus opening up possibilities for safer drug treatments.
Clyde W Yancy - One of the best experts on this subject based on the ideXlab platform.
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initiation continuation or withdrawal of angiotensin converting Enzyme Inhibitors angiotensin receptor blockers and outcomes in patients hospitalized with heart failure with reduced ejection fraction
Journal of the American Heart Association, 2017Co-Authors: Lauren G Gilstrap, Gregg C Fonarow, Akshay S Desai, Li Liang, Roland A Matsouaka, Adam D Devore, Eric E Smith, Paul A Heidenreich, Adrian F Hernandez, Clyde W YancyAbstract:BackgroundGuidelines recommend continuation or initiation of guideline‐directed medical therapy, including angiotensin‐converting Enzyme Inhibitors/angiotensin II receptor blockers (ACEi/ARB), in h...
Giacomo D Simonetti - One of the best experts on this subject based on the ideXlab platform.
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pregnancy outcome following exposure to angiotensin converting Enzyme Inhibitors or angiotensin receptor antagonists a systematic review
Hypertension, 2012Co-Authors: Marina Bullo, Sibylle Tschumi, Barbara S Bucher, Mario G Bianchetti, Giacomo D SimonettiAbstract:The objective was to analyze the outcome following prenatal exposure to angiotensin-converting Enzyme Inhibitors (ACE-Is) or angiotensin receptor antagonists (ARBs). For this purpose, a systematic review of published case reports and case series dealing with intrauterine exposure to ACE-Is or to ARBs using Medline as the source of data was performed. The publications retained for analysis included patients who were described individually, revealing, at minimum, the gestational age, substance used, period of medication intake, and the outcome. In total, 72 reports were included; 37 articles (118 well-documented cases) described the prenatal exposure to ACE-Is; and 35 articles (68 cases) described the prenatal exposure to ARBs. Overall, 52% of the newborns exposed to ACE-Is and 13% of the newborns exposed to ARBs did not exhibit any complications (P<0.0001). Neonatal complications were more frequent following exposure to ARBs and included renal failure, oligohydramnios, death, arterial hypotension, intrauterine growth retardation, respiratory distress syndrome, pulmonary hypoplasia, hypocalvaria, limb defects, persistent patent ductus arteriosus, or cerebral complications. The long-term outcome is described as positive in only 50% of the exposed children. Fetopathy caused by exposure to ACE-Is or ARBs has relevant neonatal and long-term complications. The outcome is poorer following exposure to ARBs. We propose the term "fetal renin-angiotensin system blockade syndrome" to describe the related clinical findings. Thirty years after the first description of ACE-I fetopathy, relevant complications are, at present, regularly described, indicating that the awareness of the deleterious effect of prenatal exposure to drugs inhibiting the renin-angiotensin system should be improved.