Abstract:
:Various pharmacokinetic models, both simple and complex, have been developed to describe the way in which the rate of hepatic elimination of drugs depends on hepatic blood flow, hepatic intrinsic clearance and unbound fraction of drug in blood. A model is necessary because it is not possible to measure the average blood concentration of drug within the liver, i.e. the concentration at the site of drug elimination. However, the predictions of these models can differ markedly for drugs of high hepatic clearance, especially with the oral route of administration. Investigations of the models have mostly involved studies with in vitro experimental preparations, such as isolated perfused livers. While such studies have advanced our understanding of the mechanism of hepatic uptake and elimination processes, the implications for clinical drug usage have been somewhat neglected. Use of one of the available models is necessary for the assessment of the capacity of in vivo hepatic drug metabolism processes (i.e. hepatic intrinsic clearance) and for predicting the effect of increasing dose on blood concentrations of high clearance drugs exhibiting Michaelis-Menten elimination kinetics, especially those that undergo a nonlinear hepatic first-pass effect. Clinically significant differences between the models can occur under these circumstances. A model is also required for quantitative prediction of the effect on blood drug concentrations of changes in hepatic blood flow, hepatic intrinsic clearance or drug-protein binding in blood. It is in predicting these changes that differences of major clinical significance can occur between the models. The greatest differences are seen in predicting the effect for orally administered drugs of changes of hepatic blood flow on blood concentrations, and changes of protein binding on unbound blood concentrations of drug. These changes can result from disease processes, altered physiology (old age or pregnancy), food intake or concomitant administration of other drugs. A model is also required for determining the mechanism by which such clinical changes occur. When considering these effects on hepatic elimination, it is essential to appreciate that the conclusions may depend markedly on the particular model chosen. Until more data on the applicability of the models are obtained in humans, the undistributed sinusoidal and venous equilibrium models, which represent the opposite extremes of behaviour among the available models, should both be used in assessing hepatic drug elimination.
journal_name
Clin Pharmacokinetjournal_title
Clinical pharmacokineticsauthors
Morgan DJ,Smallwood RAdoi
10.2165/00003088-199018010-00004subject
Has Abstractpub_date
1990-01-01 00:00:00pages
61-76issue
1eissn
0312-5963issn
1179-1926journal_volume
18pub_type
杂志文章,评审abstract:BACKGROUND:Entecavir is an orally administered guanosine nucleoside analog with activity against hepatitis B virus (HBV) polymerase, which is approved for the treatment of chronic hepatitis B (CHB) infection in adults and children ≥2 years old (USA and EU). OBJECTIVE:To develop simplified entecavir dosing recommendati...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.1007/s40262-016-0420-5
更新日期:2016-12-01 00:00:00
abstract:OBJECTIVE:To assess any pharmacokinetic interactions between loperamide and saquinavir. DESIGN:Double-blind, double-dummy, randomised, placebo-controlled, three-way crossover trial. PARTICIPANTS:Twelve healthy male and female volunteers, aged 24-46 years. METHODS:Saquinavir and loperamide pharmacokinetics were deter...
journal_title:Clinical pharmacokinetics
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.2165/00003088-200443140-00004
更新日期:2004-01-01 00:00:00
abstract::Interpatient pharmacokinetic variability normally observed in adults is often of even greater magnitude in paediatric patients because of age-related maturation of physiological processes responsible for drug disposition. Several antineoplastic agents have shown age-related changes, including alterations in volume of ...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-198712030-00002
更新日期:1987-03-01 00:00:00
abstract::Despite contributing significantly to the burden of global disease, the translation of new treatment strategies for diseases of the central nervous system (CNS) from animals to humans remains challenging, with a high attrition rate in the development of CNS drugs. The failure of clinical trials for CNS therapies can b...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.1007/s40262-018-0632-y
更新日期:2018-09-01 00:00:00
abstract::Aminoglycoside antibiotics are very important in the treatment of Gram-negative infections and as synergistic agents for the treatment of staphylococcal and streptococcal (group B streptococci and enterococci) infections. However, these agents have a narrow therapeutic index. Thus, a number of new antibiotics have bee...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-199426010-00006
更新日期:1994-01-01 00:00:00
abstract::Ertugliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), is approved in the US, EU, and other regions for the treatment of adults with type 2 diabetes mellitus (T2DM). This review summarizes the ertugliflozin pharmacokinetic (PK) and pharmacodynamic data obtained during phase I clinical developm...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.1007/s40262-020-00875-1
更新日期:2020-08-01 00:00:00
abstract::Haloperidol has been used extensively for the treatment of psychotic disorders, and it has been suggested that the monitoring of plasma haloperidol concentration is clinically useful. Different assay methodologies have been used in research and clinical practice to examine the relationship between response and plasma ...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-198917060-00004
更新日期:1989-12-01 00:00:00
abstract::Dorzolamide is a carbonic anhydrase inhibitor for topical ophthalmic application. It is used in the treatment of glaucoma to lower the intraocular pressure. After absorption via the cornea and stroma, it inhibits carbonic anhydrase in the ciliary process, which leads to a reduction of aqueous humour production and the...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-200241030-00004
更新日期:2002-01-01 00:00:00
abstract:BACKGROUND:Hydroxychloroquine is an oral drug prescribed to pregnant women with rheumatic disease to reduce disease activity and prevent flares. Physiologic changes during pregnancy may substantially alter drug pharmacokinetics. However, the effect of pregnancy on hydroxychloroquine disposition and the potential need f...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.1007/s40262-018-0712-z
更新日期:2019-04-01 00:00:00
abstract:BACKGROUND AND OBJECTIVE:Understanding pharmacokinetic disposition of cefepime, a β-lactam antibiotic, is crucial for developing regimens to achieve optimal exposure and improved clinical outcomes. This study sought to develop and evaluate a unified population pharmacokinetic model in both pediatric and adult patients ...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.1007/s40262-020-00873-3
更新日期:2020-08-01 00:00:00
abstract::Inpatients (n = 57) on long term prophylaxis with 2 oral phenytoin preparations were followed up via monthly checks of serum drug concentrations. Duplicate serum aliquots were submitted to 2 laboratories, and covariance analysis was used to estimate laboratory error. The laboratory-associated variance of examinations ...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.2165/00003088-199120040-00007
更新日期:1991-04-01 00:00:00
abstract::Intestinal metabolism can limit oral bioavailability of drugs and increase the risk of drug interactions. It is therefore important to be able to predict and quantify it in drug discovery and early development. In recent years, a plethora of models-in vivo, in situ and in vitro-have been discussed in the literature. T...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.1007/s40262-015-0351-6
更新日期:2016-06-01 00:00:00
abstract::The hypolipidaemic agent pravastatin differs from other US Food and Drug Administration (FDA)-approved HMG-CoA reductase inhibitors (e.g. lovastatin and simvastatin) because it has greater hydrophilicity, as a result of the hydroxyl group attached to its decalin ring. The hydrophilic nature of pravastatin accounts for...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-199427020-00002
更新日期:1994-08-01 00:00:00
abstract:BACKGROUND AND OBJECTIVES:Numerous population pharmacokinetic (PK) models of tacrolimus in adult transplant recipients have been published to characterize tacrolimus PK and facilitate dose individualization. This study aimed to (1) investigate clinical determinants influencing tacrolimus PK, and (2) identify areas requ...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.1007/s40262-020-00922-x
更新日期:2020-11-01 00:00:00
abstract::Bioequivalence of drug formulations plays an important role in drug development. Recently, the Biopharmaceutical Classification System (BCS) has been implemented for the purpose of waiving bioequivalence studies on the basis of the solubility and gastrointestinal permeability of drug substance. Using the rationale of ...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-200443150-00004
更新日期:2004-01-01 00:00:00
abstract::The relative bioavailability of a single oral dose of temafloxacin given with and without enteral feeding was determined in 18 healthy male volunteers in a randomised crossover study. Subjects were administered 600mg of temafloxacin orally as an intact tablet, or a crushed tablet suspended in water administered throug...
journal_title:Clinical pharmacokinetics
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.2165/00003088-199200221-00008
更新日期:1992-01-01 00:00:00
abstract::25 patients with different degrees of chronic stable renal failure received oral treatment with cimetidine over 6 days and a final dose in the morning of day 7. The doses of cimetidine were reduced according to the degree of renal failure. Plasma concentrations of cimetidine were determined before the morning dose on ...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.2165/00003088-198106040-00006
更新日期:1981-07-01 00:00:00
abstract:BACKGROUND AND OBJECTIVES:Tesamorelin is a synthetic analogue of growth hormone-releasing factor (GRF), which increases basal and pulsatile growth hormone (GH) secretion and subsequently increases insulin-like growth factor (IGF)-1. Limited information is available about the pharmacokinetics of this compound. Consequen...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,随机对照试验
doi:10.1007/s40262-014-0202-x
更新日期:2015-03-01 00:00:00
abstract::Dasabuvir is a nonstructural (NS) 5B non-nucleoside inhibitor of the hepatitis C virus (HCV) used in combination with ombitasvir/paritaprevir/ritonavir for the treatment of chronic HCV infection. It is primarily metabolized by cytochrome P450 (CYP) 2C8, with a minor contribution from CYP3A. Biotransformation of dasabu...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.1007/s40262-017-0519-3
更新日期:2017-10-01 00:00:00
abstract:BACKGROUND AND OBJECTIVE:Vicriviroc is a small-molecule CCR5 antagonist currently in development for the treatment of HIV in patients on a regimen containing a ritonavir-boosted protease inhibitor. As renal disease and renal dysfunction are prevalent in the HIV-infected population, patients with varying degrees of rena...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,随机对照试验
doi:10.2165/11319470-000000000-00000
更新日期:2010-06-01 00:00:00
abstract:BACKGROUND AND OBJECTIVE:Clearance is an important pharmacokinetic concept for scaling dosage, understanding the risks of drug-drug interactions and environmental risk assessment in children. Accurate clearance scaling to children requires prior knowledge of adult clearance mechanisms and the age-dependence of physiolo...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.2165/00003088-200645070-00004
更新日期:2006-01-01 00:00:00
abstract:BACKGROUND:People living with human immunodeficiency virus are ageing under combination antiretroviral treatments but data on drug exposure in serum and cerebrospinal fluid are limited. Dolutegravir is a widely used second-generation integrase strand transfer inhibitor: conflicting data suggest that neuropsychiatric si...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.1007/s40262-020-00916-9
更新日期:2021-01-01 00:00:00
abstract::Doxycycline and minocycline are second-generation tetracyclines. They are readily absorbed, distributed throughout the organism as a function of their lipophilicity and eliminated in both the urine and the faeces. The influence of age, renal disease, malnutrition and hyperlipidaemia is reviewed, together with the main...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-198815060-00001
更新日期:1988-12-01 00:00:00
abstract::Obesity is associated with physiological changes that can alter the pharmacokinetic parameters of many drugs. Vancomycin and the aminoglycosides are the only antibacterials that have been extensively investigated in the obese population. The apparent volume of distribution (Vd) and total body clearance of vancomycin a...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-200038050-00003
更新日期:2000-05-01 00:00:00
abstract:INTRODUCTION:Renal impairment may have a significant impact on the pharmacokinetics of drugs. Ad hoc studies in subjects with renal impairment are required by the regulatory authorities to propose dose adjustments in these subjects, to find a dosing regimen able to provide a systemic exposure similar to those in subjec...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.1007/s40262-017-0574-9
更新日期:2018-04-01 00:00:00
abstract::The pharmacokinetics of CRP was tested in small short-term studies in both healthy volunteers and in subjects with schizophrenia, with similar results [242]. ...
journal_title:Clinical pharmacokinetics
pub_type: 已发布勘误
doi:10.1007/s40262-019-00797-7
更新日期:2019-09-01 00:00:00
abstract::Vemurafenib is an orally administered small-molecule inhibitor of the oncogenic BRAF kinase that is indicated for the treatment of patients with unresectable or metastatic melanoma harbouring BRAF V600 mutations. Vemurafenib is absorbed rapidly after a single oral dose of 960 mg, reaching maximum drug concentration ap...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.1007/s40262-017-0523-7
更新日期:2017-09-01 00:00:00
abstract:BACKGROUND:Fondaparinux sodium is a novel antithrombotic agent, the first of a new class of selective factor Xa inhibitors. It has favourable pharmacokinetics including 100% bioavailability, low variability and a mean terminal half-life of 17 hours for young and 21 hours for elderly healthy volunteers, enabling once-da...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.2165/00003088-200241002-00002
更新日期:2002-01-01 00:00:00
abstract::Platelets contribute significantly to arterial-occlusive thrombosis, one of the major causes of death and disease throughout the world. Consequently, inhibiting platelet function is a potentially important therapeutic goal. Among agents that inhibit platelet function, ticlopidine shows a wide spectrum of antiplatelet ...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-199426050-00003
更新日期:1994-05-01 00:00:00
abstract:OBJECTIVE:To evaluate the dose proportionality and linearity and pharmacokinetic profile of desloratadine after single oral doses over the range of 5 to 20mg. DESIGN:Single centre, randomised, open-label, 4-way crossover study in which healthy adults received single doses of desloratadine (5, 7.5, 10 and 20mg) in 4 di...
journal_title:Clinical pharmacokinetics
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.2165/00003088-200241001-00001
更新日期:2002-01-01 00:00:00