Abstract：
AIM: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. METHODS: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. RESULTS: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). CONCLUSIONS: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.
journal_name
Br J Clin Pharmacoljournal_title
British journal of clinical pharmacologyauthors
Ganesan S,Williams C,Maslen CL,Cherala Gdoi
10.1111/bcp.12017subject
Has Abstractpub_date
2013-06-01 00:00:00pages
1468-77issue
6eissn
0306-5251issn
1365-2125journal_volume
75pub_type
杂志文章abstract：:The disposition and effect of orally administered prazosin have been studied in eight women with hypertension which was uncontrolled by beta-adrenoceptor blockade during the last trimester of pregnancy. Results were compared with healthy men of similar age. The median time to peak concentration was 165 min during preg...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.1983.tb02213.x
更新日期：1983-11-01 00:00:00
abstract：AIM:Characterization of the biliary disposition of GSK1325756, using a non-invasive bile sampling technique and spectrometric analyses, to inform the major routes of metabolic elimination and to enable an assessment of victim drug interaction risk. METHOD:Sixteen healthy, elderly subjects underwent non-invasive bile c...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.2012.04352.x
更新日期：2013-02-01 00:00:00
abstract：:The effects of a single dose of sulindac 200 mg and placebo on the capsaicin-induced cough reflex were studied in a two-phase double-blind crossover study in 18 healthy subjects. Sulindac increased the threshold for capsaicin cough response significantly, but did not alter D5, peak response, or the total cough respons...
journal_title：British journal of clinical pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
doi：10.1111/j.1365-2125.1991.tb05518.x
更新日期：1991-02-01 00:00:00
abstract：AIM:To examine the predictive value of gene polymorphisms potentially linked to toxicity, clinical response, time to progression and overall survival, following cetuximab-tegafur-uracil (UFT)-irinotecan therapy. METHODS:Fifty-two patients with advanced colorectal cancer were enrolled in an ancillary pharmacogenetic st...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.2011.04141.x
更新日期：2012-05-01 00:00:00
abstract：AIM:We aimed to establish a method to assess systemic and pre-systemic cytochrome P450 (CYP) 3A activity using ineffective microgram doses of midazolam. METHODS:In an open, one sequence, crossover study, 16 healthy participants received intravenous and oral midazolam at microgram (0.001 mg intravenous and 0.003 mg ora...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/bcp.12502
更新日期：2015-02-01 00:00:00
abstract：AIMS:This study aimed to develop a population pharmacokinetic model for quantitative evaluation of the influence of genetic variants in metabolic enzymes and transporters on lamotrigine pharmacokinetics while taking into account the influence of various clinical, biochemical and demographic factors. METHODS:We include...
journal_title：British journal of clinical pharmacology
pub_type： 临床试验,杂志文章
doi：10.1111/bcp.12984
更新日期：2016-08-01 00:00:00
abstract：AIMS:To evaluate the role of reported daily dose, age and other risk factors, and to assess the value of quantifying serum transaminase activity and paracetamol (acetaminophen) concentration at initial assessment for identifying patients at risk of hepatotoxicity following repeated supratherapeutic paracetamol ingestio...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章,评审
doi：10.1111/bcp.13028
更新日期：2016-10-01 00:00:00
abstract：WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT:* Only one other study (Becker et al.) has reported on the influence of smoking cessation and smoking resumption on inhaled insulin pharmacokinetics and glucodynamics, concluding that the rapid changes associated with smoking resumption carry the risk for hypoglycaemia and thus ...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章,随机对照试验
doi：10.1111/j.1365-2125.2007.03041.x
更新日期：2008-04-01 00:00:00
abstract：:1 Self-poisoning with a selective weedkiller containing 2,4-D and mecoprop in a 39 year old man resulted in prolonged deep coma, pyrexia, hyperventilation, hypoxaemia, myotonia, skeletal muscle damage and electrocardiographic changes consistent with cardiomyopathy. 2 The admission plasma concentrations of 2,4-D and me...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.1979.tb00906.x
更新日期：1979-01-01 00:00:00
abstract：AIMS:Whereas cortical EEG effects of benzodiazepines are well characterized, information about benzodiazepine effects in other areas of the central nervous system is sparse. This study investigated the action of midazolam and its active metabolite alpha-hydroxy-midazolam on different parts of the auditory pathway in si...
journal_title：British journal of clinical pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
doi：10.1046/j.1365-2125.2000.00104.x
更新日期：2000-01-01 00:00:00
abstract：:1. Potential therapies for ischaemic stroke include agents to reduce oedema, to improve cerebral perfusion, to reduce excitotoxic damage, to minimise free-radical induced injury and to reduce complications such as deep venous thrombosis. 2. Of the anti-oedema drugs, steroids are ineffective and possibly dangerous; int...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章,评审
doi：10.1111/j.1365-2125.1992.tb05655.x
更新日期：1992-12-01 00:00:00
abstract：:1. N-hydroxylation is thought to be an essential step in the haemotoxicity of dapsone (DDS). To investigate both metabolism-dependent and cell-selective drug toxicity in vitro we have developed a three-compartment system in which an hepatic drug metabolizing system is contained within a central compartment separated b...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.1993.tb05888.x
更新日期：1993-07-01 00:00:00
abstract：:1 The inotropic effect of penbutolol, a new beta-adrenergic receptor blocking drug, has been compared with that of propranolol in two similar groups of six subjects each. 2 Inotropic changes were assessed from changes in myocardial contractility index [LV dp-dt/11 T] as well as the slope of the regression line relatin...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.1978.tb00875.x
更新日期：1978-12-01 00:00:00
abstract：:Voriconazole is an antifungal metabolised by CYP2C19 enzyme, which can be inhibited by proton-pump inhibitors (PPIs). A prospective observational study was carried out to determine the influence of PPIs on voriconazole pharmacokinetic. The 78 patients included were divided into 4 groups: omeprazole (n = 32), pantopraz...
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pub_type： 杂志文章
doi：10.1111/bcp.14267
更新日期：2020-08-01 00:00:00
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journal_title：British journal of clinical pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
doi：10.1111/j.1365-2125.1989.tb03418.x
更新日期：1989-05-01 00:00:00
abstract：AIMS:The aim of this study was to investigate the impact of new insights and revised guidelines on initial and follow-up treatment with antihyperglycaemic drugs over the period 1998-2003. METHODS:The InterAction Database (IADB), which contains pharmacy dispensing data from 53 community pharmacies in the Northern and E...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.2006.02711.x
更新日期：2006-12-01 00:00:00
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journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.1975.tb00475.x
更新日期：1975-02-01 00:00:00
abstract：:1 The influence of cimetidine (1000 mg daily) on propranolol steady state plasma levels has been studied in seven normal volunteers. Cimetidine was used as a 200 mg normal release tablet whereas propranolol was given as a 160 mg slow release formulation once daily. 2 After 1 day of cimetidine treatment (day 9 of the s...
journal_title：British journal of clinical pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
doi：10.1111/j.1365-2125.1981.tb01307.x
更新日期：1981-12-01 00:00:00
abstract：:1. The single dose pharmacokinetics of orally administered nimodipine (60 mg) were investigated in normal subjects and in two groups of epileptic patients receiving chronic treatment with hepatic microsomal enzyme-inducing anticonvulsants (carbamazepine, phenobarbitone or phenytoin) and sodium valproate, respectively....
journal_title：British journal of clinical pharmacology
pub_type： 临床试验,杂志文章
doi：10.1111/j.1365-2125.1991.tb03908.x
更新日期：1991-09-01 00:00:00
abstract：:The effects of two single oral doses of ibopamine (150 and 600 mg) on heart rate, blood pressure, urine flow, sodium, potassium and creatinine excretion were studied in normal volunteers. No significant change was observed in urine flow, sodium, potassium or creatinine excretion at either dose. No significant change w...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.1984.tb02402.x
更新日期：1984-06-01 00:00:00
abstract：AIMS:Azathioprine, mercaptopurine and thioguanine are commonly used to treat autoimmune disorders, leukaemia and solid organ transplantation. However, azathiopurine and its metabolites can also cause adverse reactions such as myelosuppression. These manifestations may be attributed to polymorphisms or mutations in the ...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.2009.03405.x
更新日期：2009-07-01 00:00:00
abstract：:1. The influence of food on the absorption of frusemide and bumetanide was compared in two separate randomized crossover studies. 2. On three separate occasions frusemide 40 mg was administered to eight healthy male volunteers intravenously, orally in the fasting state and orally after a standard breakfast. Blood and ...
journal_title：British journal of clinical pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
doi：10.1046/j.1365-2125.1996.00494.x
更新日期：1996-12-01 00:00:00
abstract：:Obesity is a major cause of morbidity and mortality through cardio- and cerebrovascular diseases and cancer. The metabolic consequences of obesity include dyslipidaemia, hypertension, proinflammatory atherogenesis, pre-diabetes and Type 2 diabetes. For a significant proportion of patients, pharmacotherapy to tackle ob...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.2009.03549.x
更新日期：2009-12-01 00:00:00
abstract：:Eleven HIV-infected men participated in a randomized, two-treatment, two-period crossover study to determine the effect of a 25 g protein meal on zidovudine pharmacokinetics. On two separate occasions, 1 week apart, each patient received 200 mg zidovudine in a fasting state or immediately following the protein meal. A...
journal_title：British journal of clinical pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
doi：10.1111/j.1365-2125.1992.tb04097.x
更新日期：1992-06-01 00:00:00
abstract：AIMS:Antidepressant use has increased in the last decade. Several studies have suggested a possible association between maternal antidepressant use and teratogenic effects. METHODS:The pharmacy prescription database IADB.nl was used for a cohort study in which laxative and antidiarrhoeal medication use in children aft...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章,评审
doi：10.1111/j.1365-2125.2011.04081.x
更新日期：2012-01-01 00:00:00
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journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.1984.tb02548.x
更新日期：1984-11-01 00:00:00
abstract：:1. The pharmacokinetics and pharmacodynamics of a single dose of trandolapril, an angiotensin converting enzyme (ACE) inhibitor with an active metabolite, trandolaprilat, which is in part further metabolised prior to renal elimination, were evaluated in 31 subjects with a wide range of renal function (creatinine clear...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：
更新日期：1993-02-01 00:00:00
abstract：:The effect of acute migraine attack and rectally given metoclopramide on the absorption of orally given tolfenamic acid (300 mg) was investigated in seven female patients in a crossover study consisting of four phases, two without migraine and two during migraine. Metoclopramide hydrochloride (20 mg) or placebo was gi...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.1984.tb05001.x
更新日期：1984-01-01 00:00:00
abstract：:Pharmacological interactions in both directions between phenprocoumon and atenolol and metoprolol were investigated using a crossover trial. Co-administration of phenprocoumon did not significantly affect Cmax, tmax, t1/2,22, AUC for atenolol or metoprolol. Co-administration of metoprolol, but not atenolol, increased ...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.1984.tb02439.x
更新日期：1984-01-01 00:00:00
abstract：:1 Previous studies of propranolol disposition in renal failure have been conflicting. 2 Using simultaneous administration of [3H]-propranolol intravenously and unlabelled propranolol orally the principal determinants of drug distribution were calculated in normals, patients with severe renal impairment (creatinine cle...
journal_title：British journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1111/j.1365-2125.1980.tb00511.x
更新日期：1980-12-01 00:00:00
