Concentrations Of Active Metabolite Research Articles

Pharmacokinetic and Pharmacodynamic Effects of Prasugrel in Healthy Korean Males

Prasugrel is a thienopyridine for treatment of acute coronary syndromes in patients undergoing percutaneous coronary intervention. Higher concentrations of prasugrel's active metabolite (R-138727) have been observed in Asian than white subjects. The primary objective was to investigate pharmacokinetics of R-138727 in healthy Korean males. Thirty subjects were randomized (1:2) to a 60 or 30 mg loading dose, subsequently (1:1:1) to 10-, 7.5-, or 5-mg maintenance doses. R-138727 plasma concentrations were analyzed with liquid chromatography/mass spectrometry. Platelet aggregation was measured with Accumetrics VerifyNow. Mean (coefficient of variation) exposure to R-138727 was 600 ng·h/mL (16%) after 60 mg prasugrel and 283 ng·h/mL (17%) after 30 mg. After 10, 7.5, and 5 mg, mean exposures were 78.1 (24%), 58.4 (21%), and 38.3 ng·h/mL (24%). Pharmacokinetics were linear over this range. Daily 5 mg doses maintained a 65% (SD = 14.5%) inhibition of adenosine diphosphate-induced platelet aggregation; all other doses produced ≥90%. Prasugrel was well tolerated with no serious adverse events. Results are consistent with other studies of Asian subjects administered prasugrel. Although further guidance will be provided by a recently completed phase 3 study, these preliminary data suggest that dosing strategies approved for white patients with acute coronary syndromes are applicable to Asian patients.

Clopidogrel variability: role of plasma protein binding alterations

The large inter-individual variability in clopidogrel response is attributed to pharmacokinetics. Although, it has been used since the late 1990s the pharmacokinetic fate of clopidogrel and its metabolites are poorly explained. The variable response to clopidogrel is believed to be multi-factorial, caused both by genetic and non-genetic factors. In this study, we examined whether the inactive metabolite can alter the plasma protein binding of the active metabolite, thus explaining the large inter-individual variability associated with clopidogrel response. Female subjects (n = 28) with stable coronary disease who were not taking clopidogrel were recruited. Serial blood samples were collected following 300 mg oral dose of clopidogrel, plasma was isolated and quantified for total and free concentrations of active and inactive metabolites. Inhibition of platelet aggregation was measured using the phosphorylated vasodilator stimulated phosphoprotein (VASP) assay. A significant correlation was observed between VASP and both free (r = 0.49, P < 0.05) and total (r = 0.49, P < 0.05) concentrations of the active metabolite. Surprisingly, we observed a significant correlation with both free (r = 0.42, P < 0.05) and total (r = 0.67, P < 0.001) concentrations of the inactive metabolite as well. Free fractions of the active metabolite rose with increasing protein binding of the inactive metabolite (P < 0.05). The above in vivo data suggest that the inactive metabolite displaces the active metabolite from binding sites. Thus, the inactive metabolite might increase the free concentration of the active metabolite leading to enhanced inhibition of platelet aggregation. The plasma protein binding mechanism would offer an additional therapeutic strategy to optimize clopidogrel pharmacotherapy.

In vitro antimycotic activity of a new isolate Streptomyces fradiae MTCC 11051 against the multi-drug resistant pathogenic fungi

BackgroundIsolation of naturally occurring Streptomyces sp. with an ability to produce metabolites having antimycotic property against the pathogenic fungus from unexplored area of Chhattisgarh. MethodsStarch casein nitrate medium was used for isolation and screened for their antifungal activity by agar well diffusion method. Active isolate characterized based on the morphological, physiological and 16S rRNA sequencing. Optimization of extracellular antifungal metabolite production in terms of zone of inhibition (mm) using Candida albicans MTCC 183 as target organisms was performed and extracted with n-butanol. The minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) of active metabolite was determined according to NCCLS. Results and discussionThe active isolate was identified as Streptomyces fradiae MTCC 11051, showed the best antifungal activity against yeasts and molds including dermatophytes which showed an inimitable and stable inhibitory activity in Starch casein nitrate broth. The maximum extracellular active metabolite production was achieved in the late log phase, which remained constant during the stationary phase. The MIC and MFC values of the culture supernatant were recorded between range 50 and 100 μg/ml. ConclusionsThe metabolite from S. fradiae was active against pathogenic fungus with a greater potency. These results confirmed the therapeutic potential of bioactive fermented products can be used in medicinal and pharmaceutical preparations for treating the fungal infections.

Investigation of drug–drug interactions between clopidogrel and fluoxetine

Drug-drug interactions may contribute to the variability of the response of clopidogrel. Several hypotheses have been proposed concerning the potential modification of clopidogrel pharmacokinetics and pharmacodynamics by fluoxetine. This open-label crossover study assessed the effect of fluoxetine on the pharmacological activity of clopidogrel in healthy volunteers. Eight healthy male volunteers received a single 600-mg loading dose of clopidogrel followed by 20 mg of fluoxetine on 4 days and then 20 mg of fluoxetine plus 600 mg of clopidogrel on the fifth day. Eleven blood samples were withdrawn after clopidogrel administration to determine plasma concentrations of clopidogrel active metabolite (CAM) and platelet function. Platelet aggregation was measured by light transmittance aggregometry (LTA) and platelet reactivity index by flow cytometric vasodilator-stimulated phosphoprotein (VASP) analysis. The areas under the curve and maximum plasma concentrations of CAM were, respectively, 20.6 and 25.3% lower after co-administration of fluoxetine compared with administration of clopidogrel alone. The percentage maximum platelet aggregation values in the presence of 5 μM and 10 μM adenosine diphosphate, measured by LTA, were, respectively, 13.9 and 22.4% lower after fluoxetine co-administration. The platelet reactivity index measured by the flow cytometric VASP method was 36.8% lower when clopidogrel was administered in conjunction with fluoxetine.

Impact of aspirin dose on adenosine diphosphate-mediated platelet activities

Different aspirin dosing regimens have been suggested to impact outcomes when used in combination with adenosine diphosphate (ADP) P2Y12 receptor antagonists. Prior investigations have shown that not only aspirin, but also potent ADP P2Y12 receptor blockade can inhibit thromboxane A2-mediated platelet activation. The impact of aspirin dosing on ADP mediated platelet activities is unknown and represents the aim of this in vitro pilot pharmacodynamic (PD) investigation. Twenty-six patients with stable coronary artery disease on aspirin 81 mg/day and P2Y12 naïve were enrolled. PD assessments were performed at baseline, while patients were on 81 mg/day aspirin and after switching to 325 mg/day for 7 ± 2 days with and without escalating concentrations (vehicle, 1, 3, and 10 μM) of prasugrel's active metabolite (P-AM). PD assays included flow cytometric assessment of VASP to define the platelet reactivity index (PRI) and the Multiplate Analyzer (MEA) using multiple agonists [ADP, ADP + prostaglandin (PGE1), arachidonic acid (AA), and collagen]. Escalating P-AM concentrations showed incremental platelet P2Y12 inhibition measured by VASP-PRI (p<0.001). However, there were no differences according to aspirin dosing regimen at any P-AM concentration (vehicle: p=0.899; 1 μM: p=0.888; 3 μM: p=0.524; 10 μM: p=0.548). Similar findings were observed in purinergic markers assessed by MEA (ADP and ADP+PGE1). P-AM addition significantly reduced AA and collagen induced platelet aggregation (p<0.001 for all measures), irrespective of aspirin dose. In conclusion, aspirin dosing does not appear to affect PD measures of ADP-mediated platelet reactivity irrespective of the degree of P2Y12 receptor blockade. P2Y12 receptor blockade modulates platelet reactivity mediated by alternative activators.

High on-treatment platelet reactivity (HPR): What does it mean, and does it matter?

2013; 109: 347-355. In this issue of Thrombosis and Haemostasis, Saucedo et al. (1) demonstrate that the prevalence of high on-treatment platelet reactivity was decreased after changing clopidogrel to prasugrel. It is perhaps appealing that the patients with adverse “high on-treatment platelet reactivity (HPR)” with clopidogrel was reduced when switched to prasugrel. From a scientific point of view, the meaning of “HPR” is still unclear. This uncertainty is derived from an arguably confusing clinical development history of the thienopyridine-type antiplatelet agents (ticlopidine, clopidogrel, and prasugrel). Indeed, the use of these agents was greatly expanded based on the clinical experience, rather than on their mechanistic understanding. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE)was published in 1996 (2). However, the precise mechanism of antiplatelet action exerted by clopidogrel was clarified only after cloning the target ADP receptor of P2Y12 in 2001 (3). Moreover, the extent of P2Y12 ADP receptor blockade by active metabolite of clopidogrel in an individual patient, which should be a real bio-marker for this drug, has been measured in a very limited number of studies only (4). Nonetheless, some uncertainty remains about how much percentage of P2Y12 receptor should be blocked to achieve appropriate antithrombotic effects in individual patients. Obviously, the goal is not to achieve 100% inhibition of P2Y12 because P2Y12 deficiency manifests as a bleeding disorder (5). Perhaps some focus should be on the drugs per se. Both clopidogrel and prasugrel are pro-drugs. The chemical structure of active metabolite(s) of clopidogrel was detected in 2002 (6). Since the active metabolite(s) of clopidogrel are very labile in character with a reactive thiol function, it is most likely that the majority of produced active metabolite(s) easily binds to P2Y12 receptors on platelets circulating in liver, where it is produced (▶ Figure 1A) Thus, plasma concentrations of active metabolite(s) per se would not necessarily be good pharmaco-dynamic marker(s) for the antiplatelet effects of clopidogrel (8). Thus, the extent of P2Y12 receptor blockage, once achieved in the liver circulation, would be the same in platelet circulating in peripheral blood.

Carboxylesterase 1 as a Determinant of Clopidogrel Metabolism and Activation

Clopidogrel pharmacotherapy is associated with substantial interindividual variability in clinical response, which can translate into an increased risk of adverse outcomes. Clopidogrel, a recognized substrate of hepatic carboxylesterase 1 (CES1), undergoes extensive hydrolytic metabolism in the liver. Significant interindividual variability in the expression and activity of CES1 exists, which is attributed to both genetic and environmental factors. We determined whether CES1 inhibition and CES1 genetic polymorphisms would significantly influence the biotransformation of clopidogrel and alter the formation of the active metabolite. Coincubation of clopidogrel with the CES1 inhibitor bis(4-nitrophenyl) phosphate in human liver s9 fractions significantly increased the concentrations of clopidogrel, 2-oxo-clopidogrel, and clopidogrel active metabolite, while the concentrations of all formed carboxylate metabolites were significantly decreased. As anticipated, clopidogrel and 2-oxo-clopidogrel were efficiently hydrolyzed by the cell s9 fractions prepared from wild-type CES1 transfected cells. The enzymatic activity of the CES1 variants G143E and D260fs were completely impaired in terms of catalyzing the hydrolysis of clopidogrel and 2-oxo-clopidogrel. However, the natural variants G18V, S82L, and A269S failed to produce any significant effect on CES1-mediated hydrolysis of clopidogrel or 2-oxo-clopidogrel. In summary, deficient CES1 catalytic activity resulting from CES1 inhibition or CES1 genetic variation may be associated with higher plasma concentrations of clopidogrel-active metabolite, and hence may enhance antiplatelet activity. Additionally, CES1 genetic variants have the potential to serve as a biomarker to predict clopidogrel response and individualize clopidogrel dosing regimens in clinical practice.

Role and pharmacologic significance of cytochrome P‐450 2D6 in oxidative metabolism of toremifene and tamoxifen

We investigated the in vitro metabolism and estrogenic and antiestrogenic activity of toremifene (TOR), tamoxifen (TAM) and their metabolites to better understand the potential effects of cytochrome P-450 2D6 (CYP2D6) status on the activity of these drugs in women with breast cancer. The plasma concentrations of TOR and its N-desmethyl (NDM) and 4-hydroxy (4-OH) metabolites during steady-state dosing with TOR were also determined. Unlike TOR, TAM and its NDM metabolite were extensively oxidized to 4-OH TAM and 4-OH-NDM TAM by CYP2D6, and the rate of metabolism was affected by CYP2D6 status. 4-OH-NDM TOR concentrations were not measurable at steady state in plasma of subjects taking 80 mg of TOR. Molecular modeling provided insight into the lack of 4-hydroxylation of TOR by CYP2D6. The 4-OH and 4-OH-NDM metabolites of TOR and TAM bound to estrogen receptor (ER) subtypes with fourfold to 30-fold greater affinity were 35- to 187-fold more efficient at antagonizing ER transactivation and had antiestrogenic potency that was up to 360-fold greater than their parent drugs. Our findings suggest that variations in CYP2D6 metabolic capacity may cause significant differences in plasma concentrations of active TAM metabolites (i.e., 4-OH TAM and 4-OH-NDM TAM) and contribute to variable pharmacologic activity. Unlike TAM, the clinical benefits in subjects taking TOR to treat metastatic breast cancer would not likely be subject to allelic variation in CYP2D6 status or affected by coadministration of CYP2D6-inhibiting medications.

High dose of buprenorphine in terminally ill patient with liver failure: Efficacy and tolerability

Pain in terminally ill patients with cancer can be often hard to manage, due to the unpredictable kinetics of drugs caused by progressive kidney and liver dysfunction. Plasma concentrations of active metabolites-also a cause of dangerous side effects--could be difficult to estimate. This case report holds the idea that buprenorphine, a partial agonist of m-receptors, even at high dosage, may be effective and safe to use in terminally ill patients with significant liver and kidney impairment.

Blockbuster interactions: are they bad for the patient?

This editorial refers to ‘Accelerated platelet inhibition by switching from atorvastatin to a non-CYP3A4-metabolized statin in patients with high platelet reactivity (ACCEL-STATIN) study’, by Y. Park et al. , doi:10.1093/eurheartj/ehs083 Variability in individual responsiveness to clopidogrel has been widely acknowledged and investigated in these last few years. Clopidogrel inhibits platelet activation and aggregation by directly inhibiting the platelet P2Y12 adenosine diphosphate (ADP) receptor. It has become established that a significant proportion of patients display high platelet reactivity on clopidogrel treatment and thus are exposed to a greater risk of death, myocardial infarction, and stent thrombosis.1 One source of the variability is the hepatic metabolism of clopidogrel, which is a prodrug that requires metabolic activation to generate its active thiol metabolite.2 Specifically, clopidogrel activation requires two oxidative steps involving a variety of hepatic enzymes from the cytochrome P450 (CYP) system, the major catalyst of oxidative biotransformation reactions involved in drug metabolism.3 CYP2C19 is involved in both steps and contributes to an estimated 45% of the 2-oxo-clopidogrel and 21% of active metabolite generation.4 CYP3A4/5, another CYP isoenzyme, is also a significant contributor to clopidogrel bioactivation. Loss-of-function CYP2C19 genetic variants have been associated with reduced concentrations of active drug metabolite, diminished platelet inhibition, and higher rates of adverse cardiovascular events.5 On the other hand, there is no common genetic polymorphism associated with alteration in CYP3A4 activity. Among the non-genetic sources of variability, drug–drug interaction (DDI) is one of major concern; DDI may inhibit or induce the function of CYP isoenzymes and consequently affect the response to CYP-metabolized drugs including clopidogrel.3 Hence, CYP3A4 inhibitors and inducers are considered as important candidates to interfere with clopidogrel response (Figure 1). The antifungal agents ketoconazole and itraconazole are potent inhibitors of CYP3A4. In a study conducted in healthy subjects, ketoconazole co-administration resulted …

Prasugrel versus Clopidogrel Antiplatelet Therapy after Acute Coronary Syndrome

Antithrombotic therapy is imperative in the management of patients presenting with an acute coronary syndrome (ACS). The combination of antiplatelet therapy in conjunction with antithrombotic therapy has become the standard of care in improving the morbidity and mortality of patients with an ACS and in reducing ischemic complications of percutaneous coronary intervention. Patients with an ACS are at increased risk for a recurrent event, both in-hospital and for several months afterward. Secondary prevention to reduce these events is accomplished through the establishment of appropriate medical therapy. Dual antiplatelet therapy with aspirin and adenosine 5'-diphosphate P2Y(12) receptor blockers such as ticlopidine or clopidogrel are integral components of this regimen; however, both of these thienopyridines have a relatively slow onset of action and variable bioavailability. Prasugrel, a third-generation thienopyridine approved by the US FDA in 2009, has a more rapid onset of platelet inhibition than clopidogrel and ticlopidine because of increased efficiency of prodrug-to-active metabolite conversion. The result is higher and less variable concentration of the active metabolite within 60 minutes following oral dosing. Phase II and III trials assessing the safety and efficacy of prasugrel have been completed, including JUMBO-TIMI 26, PRINCIPLE-TIMI 44, and TRITON-TIMI 38. These trials demonstrated greater inhibition of platelet aggregation and lower rates of the composite endpoint of death, non-fatal myocardial infarction, and stroke compared with clopidogrel. However, major bleeding occurred more frequently with prasugrel treatment than with clopidogrel. This review highlights the current state of evidence-based antiplatelet therapy and provides guidance on appropriate use of prasugrel in cardiovascular medicine.

A Randomized, 2-Period, Crossover Design Study to Assess the Effects of Dexlansoprazole, Lansoprazole, Esomeprazole, and Omeprazole on the Steady-State Pharmacokinetics and Pharmacodynamics of Clopidogrel in Healthy Volunteers

The aim of this study was to assess the effects of different proton pump inhibitors (PPIs) on the steady-state pharmacokinetics and pharmacodynamics of clopidogrel. Metabolism of clopidogrel requires cytochrome P450s (CYPs), including CYP2C19. However, PPIs may inhibit CYP2C19, potentially reducing the effectiveness of clopidogrel. A randomized, open-label, 2-period, crossover study of healthy subjects (n = 160, age 18 to 55 years, homozygous for CYP2C19 extensive metabolizer genotype, confined, standardized diet) was conducted. Clopidogrel 75 mg with or without a PPI (dexlansoprazole 60 mg, lansoprazole 30 mg, esomeprazole 40 mg, or, as a positive control to maximize potential interaction and demonstrate assay sensitivity, omeprazole 80 mg) was given daily for 9 days. Pharmacokinetics and pharmacodynamics were assessed on days 9 and 10. Pharmacodynamic end-points were vasodilator-stimulated phosphoprotein P2Y(12) platelet reactivity index, maximal platelet aggregation to 5 and 20 μmol/l adenosine diphosphate, and VerifyNow P2Y12 platelet response units. Pharmacokinetic and pharmacodynamic responses with omeprazole demonstrated assay sensitivity. The area under the curve for clopidogrel active metabolite decreased significantly with esomeprazole but not with dexlansoprazole or lansoprazole. Similarly, esomeprazole but not dexlansoprazole or lansoprazole significantly reduced the effect of clopidogrel on vasodilator-stimulated phosphoprotein platelet reactivity index. All PPIs decreased the peak plasma concentration of clopidogrel active metabolite (omeprazole > esomeprazole > lansoprazole > dexlansoprazole) and showed a corresponding order of potency for effects on maximal platelet aggregation and platelet response units. Generation of clopidogrel active metabolite and inhibition of platelet function were reduced less by the coadministration of dexlansoprazole or lansoprazole with clopidogrel than by the coadministration of esomeprazole or omeprazole. These results suggest that the potential of PPIs to attenuate the efficacy of clopidogrel could be minimized by the use of dexlansoprazole or lansoprazole rather than esomeprazole or omeprazole.

Platelet Function Testing and Genotyping Improve Outcome in Patients Treated With Antithrombotic Agents

The only reason P2Y12 inhibitors are administered in addition to aspirin is to improve the prevention of thrombosis. The clinical efficacy of adding clopidogrel to aspirin as a secondary prevention strategy in patients with high-risk coronary artery disease is well established.1 There are no effects of clopidogrel on any receptor other than P2Y12 to explain the magnitude of the clinical benefit. All of the established clinical effects are attributed to reduced platelet responsiveness to ADP.2 Therefore, the patient with inadequate P2Y12 inhibition determined by ex vivo testing logically has an increased risk for thrombosis. Persistent ischemic event occurrence and the irrefutable demonstration of clopidogrel antiplatelet response variability are 2 potent arguments against the widely practiced nonselective or one-size-fits-all strategy of administering clopidogrel therapy. Observational studies conducted in thousands of patients have led to an international consensus that high on-treatment platelet reactivity (HPR) to ADP is a major risk factor for post–percutaneous coronary intervention (PCI) ischemic event occurrence.3,4 Moreover, the recent 2011 American and European guidelines have given a Class IIb recommendation for platelet function testing or genotyping if the results of testing may alter management.5–7 Furthermore, the Society of Thoracic Surgeons gave a Class IIb recommendation for platelet function testing to determine the timing of surgery in patients on clopidogrel therapy (Level of Evidence C).8 These recommendations for personalizing antiplatelet therapy are unprecedented and acknowledge that a large body of data has accrued demonstrating the relation of HPR to ischemic risk in the PCI-treated patient. Finally, the evidence of diminished effectiveness of clopidogrel in poor metabolizers (those having 2 loss-of-function [LoF] cytochrome P450 [ CYP ] 2C19 alleles) has been recognized by the Food and Drug Administration (FDA) boxed warning about treatment with clopidogrel.9 Response by Krishna …

Recent advances in the pharmacogenetics of clopidogrel

Clopidogrel has been used to prevent recurrent ischemic events after acute coronary syndrome and/or coronary stent implantation. An impaired platelet response to this drug (residual high platelet reactivity) has been identified as a risk factor for recurrent ischemic events. The platelet response to clopidogrel is highly heritable (73%) suggesting a substantial genetic component. Two sequential cytochrome P450-dependent oxidative steps are required to convert clopidogrel to its active metabolite. The first step leads to the formation of 2-oxo-clopidogrel, which is then metabolized to the active metabolite. Cytochrome P450s are large highly polymorphic family of mono-oxygenases. Many alleles have been reported, and some of these are able to modify the activity of proteins, reducing or increasing the concentration of active metabolites and the drug effect. Loss-of-function variants in the hepatic cytochrome 2C19 (mainly *2 allele) system have been found to be the predominant genetic mediators of clopidogrel response. Variant carriers have higher treatment platelet reactivity and higher risk of adverse cardiac events including stent thrombosis, myocardial infarction, and death. Although value of CYP2C19 genotyping has been demonstrated in ACS population treated with PCI, there is still a wide interindividual variability within each genotype to systematically advocate this genetic testing in clinical practice. The CYP2C19*2 variant only explained 12% of the platelet response to clopidogrel. In the near future, it is highly probable that additional gene variants or epigenetic phenomenon will emerge as significant contributors to clopidogrel response that will allow recommending genetic testing for routine use. The purpose of this review is to discuss the contribution of individual genetic differences responsible for variations of action and clopidogrel efficacy.

Pharmacokinetics and pharmacodynamics following maintenance doses of prasugrel and clopidogrel in Chinese carriers of CYP2C19 variants

This open-label, two-period, randomized, crossover study was designed to determine the effect of CYP2C19 reduced function variants on exposure to active metabolites of, and platelet response to, prasugrel and clopidogrel. Ninety healthy Chinese subjects, stratified by CYP2C19 phenotype, were randomly assigned to treatment with prasugrel 10 mg or clopidogrel 75 mg for 10 days followed by 14 day washout and 10 day treatment with the other drug. Eighty-three subjects completed both treatment periods. Blood samples were collected at specified time points for measurement of each drug's active metabolite (Pras-AM and Clop-AM) concentrations and determination of inhibition of platelet aggregation (IPA) by light transmittance aggregometry. CYP2C19 genotypes were classified into three predicted phenotype groups: rapid metabolizers [RMs (*1/*1)], heterozygous or intermediate metabolizers [IMs (*1/*2, *1/*3)] and poor metabolizers [PMs (*2/*2, *2/*3)]. Pras-AM exposure was similar in IMs and RMs (90% CI 0.85, 1.03) and slightly lower in PMs than IMs (90% CI 0.74, 0.99), whereas Clop-AM exposure was significantly lower in IMs compared with RMs (90% CI 0.62, 0.83), and in PMs compared with IMs (90% CI 0.53, 0.82). IPA was more consistent among RMs, IMs and PMs in prasugrel treated subjects (80.2%, 84.2% and 80.2%, respectively) than in clopidogrel treated subjects (59.7%, 56.2% and 36.8%, respectively; P < 0.001). Prasugrel demonstrated higher active metabolite exposure and more consistent pharmacodynamic response across all three predicted phenotype groups compared with clopidogrel, confirming observations from previous research that CYP2C19 phenotype plays an important role in variability of response to clopidogrel, but has no impact on response to prasugrel.

New and Old Mechanisms Associated with Hypertension in the Elderly

Hypertension is a widely prevalent and important risk factor for cardiovascular diseases that increase with aging. The hallmark of hypertension in the elderly is increased vascular dysfunction. However, the molecular mechanisms by which increased blood pressure leads to vascular injury and impaired endothelial function are not well defined. In the present paper, we will analyze several mechanisms described in the scientific literature involved in hypertension in the elderly as endothelial dysfunction, increased oxygen delivery to tissues, inflammation, cellular apoptosis, and increased concentration of active metabolites. Also, we will focus on new molecular mechanisms involved in hypertension such as telomeres shortening, progenitor cells, circulating microparticles, and epigenetic factors that have appeared as possible causes of hypertension in the elderly. These molecular mechanisms may elucidate different origin for hypertension in the elderly and provide us with new targets for hypertension treatment.

Unraveling the Pharmacogenetics of Clopidogrel

Clopidogrel forms a cornerstone in the treatment of patients undergoing coronary stenting. Although the clinical effectiveness of clopidogrel has been shown repeatedly in large clinical trials, there appears to be a large interindividual response variability that influences the risk of atherothrombotic events.1,2 Studies3,4 have shown that differences in the plasma concentration of the active metabolite of clopidogrel are an important determinant of its antiplatelet effect. Although several environmental factors influence the formation of the active metabolite, most variation appears to be genetic.5 Numerous studies5–7 have shown that polymorphisms in genes encoding the cytochrome (CYP) p450 system, especially CYP2C19, influence bioactivation of clopidogrel and, hence, the risk of cardiovascular events, especially stent thrombosis. Still, polymorphic variation in CYP2C19 seems to explain only 5% to 11% of the response variability to clopidogrel, leaving variation in bioactivation of clopidogrel largely unexplained.5,8 Article see p 422 A new player in the pharmacogenetics of clopidogrel was introduced by Bouman et al,9 who identified paraoxonase-1 (PON1) as a major determinant of the bioactivation and clinical efficacy of clopidogrel in a series of elegant experiments and clinical studies among subjects from European descent. This hepatic esterase is associated with high-density lipoprotein and has antioxidative effects on low-density lipoprotein and macrophages. Bouman et al identified PON1 as the crucial enzyme for the bioactivation of clopidogrel, with its common Q192R polymorphism determining the rate of active thiol metabolite formation. In a case-cohort study among 41 cases with stent thrombosis and 71 control subjects, the Q allele was dose-dependently associated with lower PON1 activity and active metabolite concentrations in plasma, reduced platelet inhibition, and a higher risk of stent thrombosis. Q192R explained >70% of the response variability to clopidogrel. The authors corroborated their findings in a …

CYP2C19 But Not PON1 Genetic Variants Influence Clopidogrel Pharmacokinetics, Pharmacodynamics, and Clinical Efficacy in Post–Myocardial Infarction Patients

Reduced concentrations of clopidogrel active metabolite have been associated with diminished platelet inhibition and higher rates of adverse cardiovascular events. Paraoxonase-1 (PON1) has recently been proposed as a key enzyme for clopidogrel metabolic activation. We tested the effects of PON1 polymorphisms on clopidogrel pharmacokinetics and pharmacodynamics and the occurrence of cardiovascular outcomes in young post-myocardial infarction (MI) patients treated with clopidogrel. We genotyped PON1 (Q192R and L55M) and CYP2C19 variants in 106 patients enrolled in the PK/PD CLOVIS-2 trial. Patients were randomly exposed to a 300-mg or 900-mg clopidogrel loading dose in a crossover study design. Clopidogrel active metabolite isomer H4 (clopi-H4) and platelet function testing were measured serially after loading dose. There was no significant association between PON1 Q192R or L55M and clopi-H4 formation or antiplatelet response to clopidogrel after either loading dose. Using multivariable linear regression analyses, the CYP2C19*2 allele was the only predictor of clopi-H4 generation and platelet response irrespective of the platelet function assay. CYP2C19 loss-of-function but not PON1 variants were significantly associated with increased risk of major cardiovascular events (death, MI, and urgent coronary revascularization) occurring during long-term clopidogrel exposure in 371 young post-MI patients (age <45 years) enrolled in the AFIJI cohort (CYP2C19 loss-of-function allele carrier versus noncarrier: hazard ratio, 2.26; 95% confidence interval, 1.15-4.41, P=0.02; PON1 QQ192 versus QR/RR192: hazard ratio, 1.03; 95% confidence interval, 0.50-2.11, P=0.93; PON1 LL55 versus LM/MM55: hazard ratio, 1.52; 95% confidence interval, 0.75-3.08, P=0.24). Our study does not confirm that PON1 Q192R or L55M can influence clopidogrel pharmacokinetics or pharmacodynamics in post-MI patients.

Rifampin, but not rifabutin, may produce opiate withdrawal in buprenorphine-maintained patients

BackgroundThis series of studies examines the pharmacokinetic/pharmacodynamic interactions between buprenorphine, an opioid partial agonist increasingly used in treatment of opioid dependence, and rifampin, a medication used as a first line treatment for tuberculosis; or rifabutin, an alternative antituberculosis medication. MethodsOpioid-dependent individuals on stable doses of buprenorphine/naloxone underwent two, 24-h blood sampling studies: (1) for buprenorphine pharmacokinetics and (2) following 15 days of rifampin 600mg daily or rifabutin 300mg daily for buprenorphine and rifampin or rifabutin pharmacokinetics. ResultsRifampin administration produced significant reduction in plasma buprenorphine concentrations (70% reduction in mean area under the curve (AUC); p=<0.001) and onset of opiate withdrawal symptoms in 50% of participants (p=0.02). While rifabutin administration to buprenorphine-maintained subjects resulted in a significant decrease in buprenorphine plasma concentrations (35% decrease in AUC; p<0.001) no opiate withdrawal was seen. Compared with historical control data, buprenorphine had no significant effect on rifampin pharmacokinetics, but was associated with 22% lower rifabutin mean AUC (p=0.009), although rifabutin and its active metabolite concentrations remained in the therapeutic range. ConclusionsRifampin is a more potent inducer of buprenorphine metabolism than rifabutin with pharmacokinetic and pharmacodynamic adverse consequences. Those patients requiring rifampin treatment for tuberculosis and receiving buprenorphine therapy are likely to require an increase in buprenorphine dose to prevent withdrawal symptoms. Rifabutin administration was associated with decreases in buprenorphine plasma concentrations, but no clinically significant adverse events were observed.

Esomeprazole but Not Pantoprazole is Associated with Lower Plasma Concentrations of Clopidogrel's Active Metabolite

Esomeprazole but Not Pantoprazole is Associated with Lower Plasma Concentrations of Clopidogrel's Active Metabolite