Abstract:
:The most convenient route of drug administration is peroral. To reach their target, drug molecules must be absorbed from the gastrointestinal tract and enter the systemic circulation in sufficient quantities. For this reason, understanding and anticipating the mechanisms and factors affecting gastrointestinal absorption and metabolism are of the utmost importance in developing new drugs. In contrast to drugs, which are administered intentionally for therapeutic reasons, chemical residues in food and other matrices enter the body unintentionally. Hence, in this case, a low systemic availability would be advantageous. For many reasons, but particularly because of financial and ethical (reduced used of animals) considerations, in vitro and ex vivo approaches to this problem have been pursued over the last few years. The use of in vitro methods, however, inherently creates questions about the validity of extrapolation to the in vivo situation. The purpose of this report is to review the current status of the field and to identify major gaps in our knowledge. Currently, there are a number of in silico, in vitro, cultured cell-based and ex vivo approaches available to predict the cell permeation, absorption and gastrointestinal metabolism of molecules. Some strengths and weaknesses of these approaches are presented, together with a discussion of genetic, environmental, physiological and pathological factors responsible for interspecies and inter-individual variability in these processes. Recent advances in our understanding of active processes such as gut epithelial transporters, involved in absorption, and drug-metabolising enzymes, responsible for intestinal presystemic metabolism, are highlighted. Some major research priorities are identified, including the need for high-quality, information-rich databases against which testing methods being developed can be prevalidated and validated. Preclinical drug development is changing rapidly, and the role of in vitro and ex vivo approaches in this process is becoming increasingly more important. Methods available now are very useful in the drug discovery and development process, including lead compound selection and optimisation and in the design of very early clinical studies, but whether any of them will eventually obviate the need for clinical trials of bioavailability is still very debatable and will require their full validation. It is clear, however, that the results from such in vitro tests are important in shaping drug discovery and the early preclinical drug development process. For other environmental, industrial and household chemicals to which humans are exposed, in particular new chemicals, results from in vitro studies might be the only source of information concerning systemic availability.
journal_name
Eur J Clin Pharmacoljournal_title
European journal of clinical pharmacologyauthors
Pelkonen O,Boobis AR,Gundert-Remy U,Action COST B15 Working Group 1.doi
10.1007/s002280100369subject
Has Abstractpub_date
2001-11-01 00:00:00pages
621-9issue
9eissn
0031-6970issn
1432-1041journal_volume
57pub_type
杂志文章,评审abstract::The presence of a possible correlation between changes in left ventricular mass of hypertensive patients and the degree of blood pressure reduction with different antihypertensive drugs has been investigated in 40 outpatients by M-mode echocardiography. Ten of these, with blood pressure in normal limits with different...
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/BF00556886
更新日期:1984-01-01 00:00:00
abstract::Natural and synthetic steroids and mineralocorticoids were tested for their in vitro suppressive activity on phytohemagglutinin (PHA) stimulated lymphocytes. Three different (p less than 0.05) groups were identified. Methylprednisolone and betamethasone were very potent, dexamethasone, hydrocortisone and prednisolone ...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00542111
更新日期:1983-01-01 00:00:00
abstract::Migraine is the most common cause of vascular headache and a highly prevalent illness. In the last 20 years, the discovery of new agents has increased clinical research on migraine. In most of clinical trials that have been conducted, the efficacy was established using a placebo as a control treatment. The objective o...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章,meta分析
doi:10.1007/s00228-005-0088-5
更新日期:2006-03-01 00:00:00
abstract:AIMS:The goal of this study was to analyze persistence and the treatment-free interval in patients being prescribed biological drugs in rheumatology practices in Germany. METHODS:Patients who received a first prescription of biological drugs between 2008 and 2016 in 21 rheumatologists in Germany were included in this ...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/s00228-019-02627-y
更新日期:2019-05-01 00:00:00
abstract::A phamacokinetic study in man has been made of a new dosage form of diclofenac hydroxyethylpyrrolidine (DIEP); soluble salt packed in sachets was compared with diclofenac sodium as enteric coated tablets. Oral DIEP 2 X 50 mg showed a significant difference in absorption kinetics (ka, lag time and tmax) as compared to ...
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/BF00265987
更新日期:1990-01-01 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
abstract:OBJECTIVE:To examine the impact of medication and medical conditions on the fall risk in older hospitalized patients. DESIGN:Matched case-control study. SETTING:Large regional hospital in a mid-sized German city. SUBJECTS:Four hundred eighty-one inpatients aged ≥ 65 years who fell during hospitalization ("cases") an...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/s00228-019-02668-3
更新日期:2019-08-01 00:00:00
abstract::Drug-induced liver injury (DILI) is an event that has a detrimental impact on drug development and patient safety; therefore the identification of novel biomarkers that are both sensitive and specific to the liver would have great benefit. Inflammation is known to be associated with human cases of DILI, and given the ...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章,评审
doi:10.1007/s00228-010-0862-x
更新日期:2010-10-01 00:00:00
abstract:PURPOSE:The present study was carried out in order to assess the effects of chronic administration of flunitrazepam (as an oral hypnotic) on 24-h blood pressure (BP) and heart rate (HR) in healthy young adults. MATERIALS AND METHODS:Following a 2-week placebo run-in period, 28 healthy volunteers (13 males and 15 femal...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章,随机对照试验
doi:10.1007/s00228-018-2466-9
更新日期:2018-08-01 00:00:00
abstract::Plasma aspirin, salicylate and salicyluric acid concentrations were monitored in young, elderly and alcoholic subjects after ingestion of a single 1.2 g dose of soluble aspirin. The plasma aspirin, salicylate and unbound salicylate concentration-time profiles varied considerably between individual subjects. Most of th...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00543800
更新日期:1983-01-01 00:00:00
abstract:PURPOSE:This study aims to compare the prevalence of potentially inappropriate medicines (PIMs) and potential prescribing omissions (PPOs) using several screening tools in an Irish community-dwelling older cohort, to assess if the prevalence changes over time and to determine factors associated with any change. METHOD...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/s00228-015-1815-1
更新日期:2015-04-01 00:00:00
abstract::The effects of short-term lithium (Li) administration on alpha 2-adrenoceptor sensitivity was studied in 10 healthy volunteers and in 15 patients with normothymic, phasic depressive disorders. The GH-clonidine test was used to examine alpha 2-adrenoceptor sensitivity, administered before and after Li treatment (600 mg...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00637595
更新日期:1988-01-01 00:00:00
abstract:AIM:To analyse the consumption of a number of medicines with a known potential for increasing the risk of road traffic accidents in the general population of Europe. METHODS:Questionnaires were distributed through the European Drug Utilization Research Group (EuroDURG) and Post-Innovation Learning through Life-events ...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/s00228-009-0695-7
更新日期:2009-11-01 00:00:00
abstract::The disposition of oral metoprolol was studied in 5 women during the last trimester of pregnancy and 3 to 5 months after delivery. After a single oral dose of 100 mg the individual peak plasma concentration in the pregnant state was only 20-40% of that after pregnancy. The plasma half-lives of metoprolol were about th...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00613820
更新日期:1983-01-01 00:00:00
abstract::The pharmacokinetics of fluocortolone and its effect on the circadian rhythm of plasma cortisol and ACTH have been studied during different schedules of oral administration. Groups of 6 healthy male adults were given a single daily dose of fluocortolone 5, 10 and 20 mg, and another group received 20 mg every second da...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00609249
更新日期:1988-01-01 00:00:00
abstract::The effect of drinking grapefruit juice on the acute pharmacokinetic and haemodynamic actions of the dihydropyridine calcium antagonist felodipine given as a 5 mg plain tablet has been studied in nine, healthy, middle-aged males. Compared to water, grapefruit juice caused an increase in Cmax from mean 6 to 16 nmol.l-1...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00266354
更新日期:1992-01-01 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::The pharmacokinetics of propafenone and 5-OH-propafenone and their relationship with the antiarrhythmic action and side effects have been studied in 10 patients with stable, frequent, premature ventricular beats (224-928 premature ventricular complexes/h). Observations were made after a single dose of propafenone 300 ...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00614557
更新日期:1988-01-01 00:00:00
abstract::The effect of nomifensin (Hoechst 36984), a synthetic psychotropic drug whose structure differs from MAO inhibitors and tricyclics, was studied in a double blind comparative trial with desimipramine in patients with various depressive syndromes. Forty-three patients (23 in the nomifensin group and 20 in the desimipram...
journal_title:European journal of clinical pharmacology
pub_type: 临床试验,杂志文章
doi:10.1007/BF00609468
更新日期:1976-06-15 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:OBJECTIVE:To investigate (1) the pharmacokinetic and pharmacodynamic profiles of desmopressin in men from an age group with a high incidence of nocturia; and (2) circadian variation in the pharmacokinetic parameters. METHODS:The study had an open, randomised, four-way cross-over design. Desmopressin was administered o...
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/s00228-004-0781-9
更新日期:2004-08-01 00:00:00
abstract:PURPOSE:Oncological patients are at increasing risk of QT prolongation, a risk factor for ventricular arrhythmia. We assessed impact and risk factors for corrected QT (QTc) prolongation during multiple-cycle chemotherapy. METHODS:We enrolled 100 outpatients initiating chemotherapy in a university center specializing i...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/s00228-015-1874-3
更新日期:2015-08-01 00:00:00
abstract:PURPOSE:The quality of drug therapy is an important issue for nursing homes. This study aimed to assess the prevalence of polypharmacy and potentially inappropriate medications (PIMs) in a large sample of nursing home residents by using the data recorded during the preparation of pill dispensers. METHODS:This is a cro...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/s00228-016-2193-z
更新日期:2017-05-01 00:00:00
abstract:PURPOSE:Serotonin receptor 1B (HTR1B) is involved in the regulation of the serotonin system, playing different roles in specific areas of the brain. We review the characteristics of the gene coding for HTR1B, its product and the functional role of HTR1B in the neural networks involved in motivation and memory; the cent...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章,评审
doi:10.1007/s00228-009-0724-6
更新日期:2010-01-01 00:00:00
abstract::The effect of treatment with diflunisal on the steady-state pharmacokinetics of indomethacin has been studied in 16 healthy volunteers. The steady-state plasma concentration and AUC of indomethacin were significantly increased two- to threefold during treatment with diflunisal and its total clearance and total volume ...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00558077
更新日期:1989-01-01 00:00:00
abstract:PURPOSE:To assess the influence of the P450 oxidoreductase 28 SNP (POR 28) on tacrolimus pharmacokinetics in the Chinese population. METHODS:Seventy-one healthy Chinese volunteers enrolled in the study received an oral dose of 2 mg of tacrolimus after providing written informed consent. CYP3A5 3 was genotyped by polym...
journal_title:European journal of clinical pharmacology
pub_type: 临床试验,杂志文章
doi:10.1007/s00228-012-1432-1
更新日期:2013-04-01 00:00:00
abstract:PURPOSE:The antihypertensive effect of angiotensin-converting enzyme inhibitors (ACEi) is attributed partially to increased nitric oxide bioavailability. It is possible that functional polymorphisms in endothelial nitric oxide synthase (eNOS) and bradykinin receptor B2 (BDKRB2) genes may affect the antihypertensive res...
journal_title:European journal of clinical pharmacology
pub_type: 临床试验,杂志文章
doi:10.1007/s00228-012-1326-2
更新日期:2013-02-01 00:00:00
abstract::In a double-blind controlled trial 22 patients with mild or moderate essential hypertension were treated with nicardipine 30 mg t.d.s. and 19 patients with propranolol 80 mg t.d.s. as monotherapy for 24 weeks. Blood pressure in both groups at the end of trial was equally and significantly reduced; systolic pressure 22...
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/BF00544554
更新日期:1987-01-01 00:00:00
abstract::The effect of long-term treatment on the absorption and disposition of metoprolol has been evaluated in 8 healthy, non-smoking, elderly individuals (mean age 74.5 years) and in a control group of 8 healthy, young individuals. Two trace doses of [3H]metoprolol were given i.v., first concomitantly with a single oral 50 ...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00544048
更新日期:1984-01-01 00:00:00
abstract:OBJECTIVE:The ABCB1 (MDR1) multidrug transporter plays a key role in determining drug bioavailability. Differences in drug response exist among different ethnic groups. However, until now, no haplotype data are available in a Black African population. METHODS:Exons 2, 7, 10, 11, 12, 14, 17, 21, 26, and the surrounding...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/s00228-004-0879-0
更新日期:2005-04-01 00:00:00