Abstract:
OBJECTIVE:Knowledge about the metabolism of anti-parasitic drugs (APDs) will be helpful in ongoing efforts to optimise dosage recommendations in clinical practise. This study was performed to further identify the cytochrome P(450) (CYP) enzymes that metabolise major APDs and evaluate the possibility of predicting in vivo drug clearances from in vitro data. METHODS:In vitro systems, rat and human liver microsomes (RLM, HLM) and recombinant cytochrome P(450) (rCYP), were used to determine the intrinsic clearance (CL(int)) and identify responsible CYPs and their relative contribution in the metabolism of 15 commonly used APDs. RESULTS AND DISCUSSION:CL(int) determined in RLM and HLM showed low (r(2)=0.50) but significant ( P<0.01) correlation. The CL(int) values were scaled to predict in vivo hepatic clearance (CL(H)) using the 'venous equilibrium model'. The number of compounds with in vivo human CL data after intravenous administration was low ( n=8), and the range of CL values covered by these compounds was not appropriate for a reasonable quantitative in vitro-in vivo correlation analysis. Using the CL(H) predicted from the in vitro data, the compounds could be classified into three different categories: high-clearance drugs (>70% liver blood flow; amodiaquine, praziquantel, albendazole, thiabendazole), low-clearance drugs (<30% liver blood flow; chloroquine, dapsone, diethylcarbamazine, pentamidine, primaquine, pyrantel, pyrimethamine, tinidazole) and intermediate clearance drugs (artemisinin, artesunate, quinine). With the exception of artemisinin, which is a high clearance drug in vivo, all other compounds were classified using in vitro data in agreement with in vivo observations. We identified hepatic CYP enzymes responsible for metabolism of some compounds (praziquantel-1A2, 2C19, 3A4; primaquine-1A2, 3A4; chloroquine-2C8, 2D6, 3A4; artesunate-2A6; pyrantel-2D6). For the other compounds, we confirmed the role of previously reported CYPs for their metabolism and identified other CYPs involved which had not been reported before. CONCLUSION:Our results show that it is possible to make in vitro-in vivo predictions of high, intermediate and low CL(int) drug categories. The identified CYPs for some of the drugs provide a basis for how these drugs are expected to behave pharmacokinetically and help in predicting drug-drug interactions in vivo.
journal_name
Eur J Clin Pharmacoljournal_title
European journal of clinical pharmacologyauthors
Li XQ,Björkman A,Andersson TB,Gustafsson LL,Masimirembwa CMdoi
10.1007/s00228-003-0636-9subject
Has Abstractpub_date
2003-09-01 00:00:00pages
429-42issue
5-6eissn
0031-6970issn
1432-1041journal_volume
59pub_type
杂志文章abstract::The haemodynamic effects of prenalterol, a new beta-1 agonist, were studied in 10 patients with chronic heart failure. Following intravenous prenalterol infusions of 1 mg, 2.5 mg and 5 mg at 15 min intervals, oral slow release prenalterol 20 mg, 30 mg and 50 mg was given at 2 h intervals and then 50-100 mg bid for one...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00542125
更新日期:1983-01-01 00:00:00
abstract::The peripheral histamine-inhibiting and central sedative effects of single oral doses (SOD) and of repeated administration for one week (steady state, SS), of 20 mg hydroxyzine HCL and 10 mg cetirizine have been assessed in 12 healthy volunteers, in a double-blind placebo-controlled cross-over study. Peripheral H1-rec...
journal_title:European journal of clinical pharmacology
pub_type: 临床试验,杂志文章
doi:10.1007/BF00626365
更新日期:1991-01-01 00:00:00
abstract::A comparative pharmacokinetic study was performed with two types of suppository each containing 20 mg piroxicam. The bioavailability of piroxicam was studied in 24 healthy volunteers in a double blind, randomised, cross over study. No significant difference was found in the pharmacokinetic parameters [AUC(0-72 h), AUC...
journal_title:European journal of clinical pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1007/BF02333031
更新日期:1992-01-01 00:00:00
abstract:OBJECTIVE:To quantify the relation between local and systemic magnitudes of effects of inhaled formoterol and salbutamol. METHODS:Twenty-eight stable asthmatic patients completed this double-blind, randomised crossover study. Pre-drug administration FEV1 (mean 2.08 L) was 49-93% of predicted and reversibility 16-82% a...
journal_title:European journal of clinical pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
doi:
更新日期:2002-07-01 00:00:00
abstract:OBJECTIVE:The multidrug resistance gene 1 (MDR1) seems to play a role in the carcinogenesis of colorectal tumors. The importance of MDR1 SNPs 2677G > T/A in exon 21 and 3435C > T in exon 26 for cancer susceptibility, however, has not yet been clearly defined. METHODS:Two hundred and eighty-five colorectal cancer patie...
journal_title:European journal of clinical pharmacology
pub_type: 临床试验,杂志文章
doi:10.1007/s00228-006-0225-9
更新日期:2007-01-01 00:00:00
abstract::Pharmacokinetic and pharmacodynamic properties of a new controlled-release (CR) formulation of metoprolol have been compared with those of atenolol. Metoprolol CR (100 mg and 200 mg), atenolol (50 mg and 100 mg) and placebo were each given once daily for four days in a double-blind, cross-over study to ten healthy men...
journal_title:European journal of clinical pharmacology
pub_type: 临床试验,杂志文章
doi:10.1007/BF00578408
更新日期:1988-01-01 00:00:00
abstract::A one-compartment model with first-order absorption has provided good fits to five sets of indomethacin data and four sets of ketoprofen data taken at different times of day. There was substantial variation in the model parameters with time of administration and most of the features of this variation applied equally t...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00265955
更新日期:1993-01-01 00:00:00
abstract::The kinetics of mefloquine were studied in 12 healthy Thai male and 12 healthy Thai female volunteers. Mefloquine (MQ) was administered either alone (750 mg orally) or in combination (MSP) with sulphadoxine (1.5 g) and pyrimethamine (75 mg) to each of 6 male and 6 female subjects. Plasma concentrations of MQ were meas...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00542191
更新日期:1987-01-01 00:00:00
abstract:PURPOSE:The aim of this study was to assess the pharmacokinetics and protein binding of cefazolin in morbidly obese patients undergoing bariatric surgery, to study the influence of bodyweight measures and age on pharmacokinetic parameters and to evaluate unbound cefazolin concentrations over time in this population. M...
journal_title:European journal of clinical pharmacology
pub_type: 临床试验,杂志文章
doi:10.1007/s00228-011-1048-x
更新日期:2011-10-01 00:00:00
abstract::Milrinone, a new, nonglycosidic inotropic agent with peripheral vasodilating properties, was given as a single oral 5 mg dose to 7 healthy subjects, 7 patients with moderate renal impairment (CRI I, creatinine clearance 30-63 ml/min) and 7 patients with severe renal impairment had hypertension. The mean urinary recove...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00635891
更新日期:1986-01-01 00:00:00
abstract:PURPOSE:The role of pharmacogenomics, clinical and demographic parameters in pharmacokinetic predictions was evaluated in patients receiving mycophenolic acid (MPA). METHODS:A cohort study design of patients with glomerulonephritis secondary to lupus nephritis and anti-neutrophil cytoplasmic antibody (ANCA) vasculitis...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/s00228-010-0846-x
更新日期:2010-11-01 00:00:00
abstract:PURPOSE:We examined the extent of concurrent use of antiplatelets, anticoagulants, or digoxin with Chinese medications (CMs) and identified its associated factors. METHODS:A retrospective cohort study was conducted using one million random samples from the Longitudinal Health Insurance Database 2005 in Taiwan. High-ri...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/s00228-012-1359-6
更新日期:2013-03-01 00:00:00
abstract::The effect of dexfenfluramine (dF) on body weight, blood pressure and noradrenergic activity were studied in 30 obese hypertensive patients randomly divided into two groups and treated for 3 months either with dF (30 mg daily; 16 subjects) or placebo (Pl; 14 subjects). 11 patients from the dF group and 9 patients give...
journal_title:European journal of clinical pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1007/BF00265922
更新日期:1992-01-01 00:00:00
abstract:PURPOSE:Ticagrelor is a reversibly binding P2Y12 receptor antagonist for the prevention of atherothrombotic events in patients with acute coronary syndrome. Previous in vitro studies showed that ticagrelor is a substrate and inhibitor of P-glycoprotein (ABCB1). Therefore, we examined the potential interaction between d...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章,随机对照试验
doi:10.1007/s00228-013-1543-3
更新日期:2013-10-01 00:00:00
abstract:PURPOSE:The purpose of this study was to investigate the interactions of itraconazole (ITCZ) with orally administered calcineurin inhibitors (CNIs) in Japanese allogeneic hematopoietic stem cell transplant (HSCT) recipients. METHODS:Sixteen HSCT patients (8 patients each receiving tacrolimus or cyclosporine) were enro...
journal_title:European journal of clinical pharmacology
pub_type: 临床试验,杂志文章
doi:10.1007/s00228-013-1471-2
更新日期:2013-06-01 00:00:00
abstract:PURPOSE:Fibroblast growth factor receptor 4 (FGFR4) expression has association with tumor malignancy. In thyroid cancers, FGFR4 has been reported to be characteristically expressed in aggressive thyroid tumors, such as anaplastic thyroid carcinoma (ATC). METHODS:We investigated FGFR4 expression in patients with ATC an...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/s00228-020-02842-y
更新日期:2020-05-01 00:00:00
abstract::The plasma kinetics of timolol administered orally and intravenously to 5 male subjects were examined. Bioavailability was reduced by 25% when the drug was taken orally. Mean plasma half-life after oral dosing was 4.86 h, and after intravenous administration it was 4.56 h; the difference was not significant. The volum...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00716385
更新日期:1978-12-18 00:00:00
abstract:BACKGROUND:Zolmitriptan is a 5HT(1B/1D) receptor agonist effective in the acute treatment of migraine. Clinical trials in the USA and Europe have demonstrated the optimal oral therapeutic dose to be 2.5 mg. The 2.5-mg oral tablet has recently been licensed in Japan. OBJECTIVE:To compare the pharmacokinetics of zolmitr...
journal_title:European journal of clinical pharmacology
pub_type: 临床试验,杂志文章,多中心研究
doi:10.1007/s00228-002-0461-6
更新日期:2002-07-01 00:00:00
abstract::We have evaluated the pharmacokinetics of high doses of clonidine, as used in the prophylactic treatment of alcohol withdrawal syndrome, in 11 alcohol-dependent patients undergoing surgery for oesophagogastrectomy. Clonidine was given in a bolus of 150 micrograms followed by a continuous infusion. After a mean period ...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00315500
更新日期:1993-01-01 00:00:00
abstract::The effect of the angiotensin converting enzyme inhibitor, perindopril, on autonomic function was assessed in a double blind, placebo controlled, crossover study in 10 normotensive males. Eight milligram of perindopril given orally lowered blood pressure without a change in heart rate. Perindopril enhanced the vagally...
journal_title:European journal of clinical pharmacology
pub_type: 临床试验,杂志文章
doi:10.1007/BF00614298
更新日期:1986-01-01 00:00:00
abstract:PURPOSE:Treatment failures following vancomycin therapy in patients with methicillin-resistant Staphylococcus aureus infections have led to the utilization of higher doses of this antibiotic to achieve the trough concentrations of 10-20 μg/mL recommended by the Infectious Diseases Society of America clinical practice g...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章,评审
doi:10.1007/s00228-012-1259-9
更新日期:2012-09-01 00:00:00
abstract:PURPOSE:The study aims to compare the efficacy and safety of capecitabine plus oxaliplatin (XELOX) with 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOXs) in patients with advanced gastric cancer. METHODS:Five databases were searched up to June 2014, without language restrictions. The outcomes included overall respo...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章,meta分析
doi:10.1007/s00228-015-1828-9
更新日期:2015-05-01 00:00:00
abstract:PURPOSE:Drug utilization studies have applied different methods to various data types to describe medication use, which hampers comparisons across populations. The aim of this study was to describe the time trends in antidepressant prescribing in the last decade and the variation in the prevalence, calculated in a unif...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章,多中心研究
doi:10.1007/s00228-014-1676-z
更新日期:2014-07-01 00:00:00
abstract::The levels of doxycycline in serum, bile and the gallbladder wall were determined in 25 patients during cholecystectomy, by means of bioassay after previous intravenous administration of doxycycline. The mean biliary level exceeded 20 microgram/ml, and the mean level in the gallbladder wall was greater than 2 microgra...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00554664
更新日期:1981-01-01 00:00:00
abstract:BACKGROUND:Tamoxifen is one of the cornerstones of endocrine therapy for breast cancer. Recently, the decreased activity CYP3A4*22 allele and the loss of function CYP3A5*3 allele have been described as potential factors that could help to explain the inter-patient variability in tamoxifen metabolism. The aim of this st...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/s00228-017-2323-2
更新日期:2017-12-01 00:00:00
abstract:PURPOSE:Few data on the efficacy and safety of drugs in children are available as in the past, these children were not included in randomized controlled trials (RCTs). Data on the efficacy and safety of drugs in children are extrapolated from adults. The EMA recognizes the need for long-term safety studies on various d...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章,评审
doi:10.1007/s00228-010-0930-2
更新日期:2011-05-01 00:00:00
abstract::The mode and site of action of the new diuretic agent piretanide were investigated in man. The effect of a single oral dose of 12 mg was compared with that of furosemide 80 mg p.o. iin 6 patients with the nephrotic syndrome. Piretanide showed a greater diuretic and natriuretic response than furosemide during maximal w...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00561895
更新日期:1980-01-01 00:00:00
abstract:OBJECTIVES:To explore the views and perspectives of children on the unlicensed/off-label use of medicines in children and on the participation of children in clinical trials. METHODS:Focus-group discussions, involving school children, were carried out in a range of primary and secondary schools in Northern Ireland. A ...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/s00228-011-1110-8
更新日期:2012-02-01 00:00:00
abstract::The pharmacokinetics of metoclopramide has been studied after acute IV administration to 12 patients with hepatic cirrhosis (6 with and 6 without ascites) and 6 control subjects. The elimination half-life was significantly longer in patients (11.4 h and 9.9 h in those with and without ascites, respectively, vs 6.4 h i...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00265857
更新日期:1991-01-01 00:00:00
abstract:OBJECTIVES:Digoxin is a well-known probe for the activity of P-glycoprotein. The objective of this work was to apply different methods for covariate selection in non-linear mixed-effect models to study the relationship between the pharmacokinetic parameters of digoxin and the genotype for two major exons located on the...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/s00228-007-0269-5
更新日期:2007-05-01 00:00:00