Abstract：
:Historically, failure rates in drug development are high; increased sophistication and investment throughout the process has shifted the reasons for attrition, but the overall success rates have remained stubbornly and consistently low. Only 8% of new entities entering clinical testing gain regulatory approval, indicating that significant obstacles still exist for efficient therapeutic development. The continued high failure rate can be partially attributed to the inability to link drug exposure with the magnitude of observed safety and efficacy-related pharmacodynamic (PD) responses; frequently, this is a result of nonclinical models exhibiting poor prediction of human outcomes across a wide range of disease conditions, resulting in faulty evaluation of drug toxicology and efficacy. However, the increasing quality and standardization of experimental methods in preclinical stages of testing has created valuable data sets within companies that can be leveraged to further improve the efficiency and accuracy of preclinical prediction for both pharmacokinetics (PK) and PD. Models of Quantitative structure-activity relationships (QSAR), physiologically based pharmacokinetics (PBPK), and PK/PD relationships have also improved efficiency. Founded on a core understanding of biochemistry and physiological interactions of xenobiotics, these in silico methods have the potential to increase the probability of compound success in clinical trials. Integration of traditional computational methods with machine-learning approaches and existing internal pharma databases stands to make a fundamental impact on the speed and accuracy of predictions during the process of drug development and approval.
journal_name
Drug Metab Revjournal_title
Drug metabolism reviewsauthors
Maharao N,Antontsev V,Wright M,Varshney Jdoi
10.1080/03602532.2020.1726944subject
Has Abstractpub_date
2020-05-01 00:00:00pages
283-298issue
2eissn
0360-2532issn
1097-9883journal_volume
52pub_type
杂志文章,评审abstract：:The reabsorptive and excretory capacity of the kidney has an important influence on the systemic concentration of drugs. Multidrug resistance proteins (MRP/ABCC) expressed in the kidney play a critical role in the tubular efflux of a wide variety of drugs and toxicants, and, in particular, of their negatively charged ...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.1080/03602530500205275
更新日期：2005-01-01 00:00:00
abstract：:Dehydroepiandrosterone has been thought to have physiological functions other than as an androgen precursor. The previous studies performed have demonstrated a number of biological effects in rodents, such as amelioration of disease in diabetic, chemical carcinogenesis, and obesity models. To date, activation of the p...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.1080/03602530600569877
更新日期：2006-01-01 00:00:00
abstract：:Numerous experimental and epidemiological studies have demonstrated that polycyclic aromatic hydrocarbons (PAHs), which are major constituents of cigarette tobacco tar, are strongly involved in the pathogenesis of the cardiovascular diseases (CVDs). Knowing that PAH-induced toxicities are mediated by the activation of...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.1080/03602530600632063
更新日期：2006-01-01 00:00:00
abstract：:This article reviews the regulatory, social, policy, and other issues that will shape the development of pharmacogenomics applications. We identify and analyze 19 key public policy issues, ranging from the economic incentives for linked diagnostic-drug development, to the regulation of tests and drugs, and to privacy ...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.1080/03602530801952500
更新日期：2008-01-01 00:00:00
abstract：:1. The metabolic activity of the gastrointestinal microflora can be modified by numerous factors derived from the host, the host's environment, and the flora itself. 2. Marked differences exist in microbial composition and metabolism of the gut floras of different species of animal, and in the degree of colonization o...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.3109/03602538808994135
更新日期：1988-01-01 00:00:00
abstract：:The efficacy of drugs has to be demonstrated following the principal approach of statistical evaluation in controlled clinical trials. This scientifically and internationally accepted numerical approach has developed over the years to its importance, in contrast to the more pharmacologically attempt to extrapolate hum...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.1081/dmr-200033500
更新日期：2004-10-01 00:00:00
abstract：:Cytochrome P450 2D6 (CYP2D6) is a polymorphic enzyme responsible for metabolizing approximately 25% of all drugs. CYP2D6 is highly expressed in the brain and plays a role as the major CYP in the metabolism of numerous brain-penetrant drugs, including antipsychotics and antidepressants. CYP2D6 activity and inhibition h...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.3109/03602532.2015.1047026
更新日期：2015-08-01 00:00:00
abstract：:Human CYP1A2 is one of the major CYPs in human liver and metabolizes a number of clinical drugs (e.g., clozapine, tacrine, tizanidine, and theophylline; n > 110), a number of procarcinogens (e.g., benzo[a]pyrene and aromatic amines), and several important endogenous compounds (e.g., steroids). CYP1A2 is subject to rev...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.3109/03602530903286476
更新日期：2010-05-01 00:00:00
abstract：:Bioconjugation of therapeutic agents has been used as a selective drug delivery platform for many therapeutic areas. Bioconjugates are prepared by the covalent linkage of active compounds (small or large molecule) to a carrier molecule (lipids, proteins, peptides, carbohydrates, and polymers) through a chemical linker...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.1080/03602532.2020.1716784
更新日期：2020-02-01 00:00:00
abstract：:Xenobiotic metabolism, a ubiquitous natural response to foreign compounds, elicits initiating signals for many pathophysiological events. Currently, most widely used techniques for identifying xenobiotic metabolites and metabolic pathways are empirical and largely based on in vitro incubation assays and in vivo radiot...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.1080/03602530701497804
更新日期：2007-01-01 00:00:00
abstract：:The rat P450IIA subfamily was characterized at the protein, cDNA, and gene level. The purified IIA1 and IIA2 P-450s displayed distinct positional specificities toward hydroxylation of the prototype substrate testosterone. The IIA1 and IIA2 genes were also regulated differently during development; IIA1 was expressed wi...
journal_title：Drug metabolism reviews
pub_type： 杂志文章
doi：10.3109/03602538909103582
更新日期：1989-01-01 00:00:00
abstract：:Population pharmacokinetics describe the typical relationships between physiology (both normal and disease altered) and pharmacokinetics, the interindividual variability in these relationships, and their residual intraindividual variability. Knowledge of population kinetics can help one to choose initial drug dosage, ...
journal_title：Drug metabolism reviews
pub_type： 杂志文章
doi：10.3109/03602538409015063
更新日期：1984-01-01 00:00:00
abstract：:Synthetic cannabinoids (SC), originally developed as research tools, are now highly abused novel psychoactive substances. We present a comprehensive systematic review covering in vivo and in vitro animal and human pharmacokinetics and analytical methods for identifying SC and their metabolites in biological matrices. ...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.3109/03602532.2015.1029635
更新日期：2015-05-01 00:00:00
abstract：:By inhibiting ACE, captopril blocks the conversion of AI or AII and augments the effects of bradykinin both in vitro and in vivo. In rats, dogs, and monkeys with 2-kidney renal hypertension, orally administered captopril rapidly and markedly reduces blood pressure; this antihypertensive effect apparently occurs via a ...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.3109/03602538409041080
更新日期：1984-01-01 00:00:00
abstract：:The CYP4 family of cytochrome P450 enzymes and the mammalian peroxidases covalently bind their heme groups. In the CYP4 enzymes this involves one, and in the peroxidases two, covalent ester links between heme methys and carboxylic acid side-chains. In addition, in myeloperoxidase, a methionine forms a sulfonium link t...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.1080/03602530802186439
更新日期：2008-01-01 00:00:00
abstract：:Mineral fibers, including asbestos, are ubiquitous contaminants of the environment. Asbestos fibers are generally present at levels below 1 fiber/L in air though 10 fibers/L may be found in cities; these levels do not appear to be high enough to present a hazard to health. These fibers come mostly from the use of fibr...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.3109/03602539408998321
更新日期：1994-01-01 00:00:00
abstract：:Glycyrrhizic acid is widely applied as a sweetener in food products and chewing tobacco. In addition, it is of clinical interest for possible treatment of chronic hepatitis C. In some highly exposed subjects, side effects such as hypertension and symptoms associated with electrolyte disturbances have been reported. To...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.1081/dmr-100104400
更新日期：2001-05-01 00:00:00
abstract：:Indirect evidence for the participation of cytochrome P450 (P450) in the microsomal N-oxygenation of primary and N-substituted amine functions is presented by studies employing diagnostic modifiers of the hemoprotein system as well as immunochemical approaches. Experiments with recombinant hemoproteins or isozymes pur...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.1081/dmr-120005646
更新日期：2002-08-01 00:00:00
abstract：:The aim of this study was to evaluate diazepam and oxazepam as cytochrome P450 inducers at doses previously shown to cause liver tumors in mice but not rats. In rats, diazepam and oxazepam induced CYP2B, and were as effective as phenobarbital despite lacking phenobarbital's tumor-promoting effect in rats. In mice, dia...
journal_title：Drug metabolism reviews
pub_type： 杂志文章
doi：10.1080/03602530600570081
更新日期：2006-01-01 00:00:00
abstract：:Voriconazole, a second-generation triazole frequently used for the prophylaxis and treatment of invasive fungal infections, undergoes complex metabolism mainly involving various (polymorphic) cytochrome P450 enzymes in humans. Although high inter- and intraindividual variability in voriconazole pharmacokinetics have b...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.1080/03602532.2019.1632888
更新日期：2019-08-01 00:00:00
abstract：:In summary, the concerns that environmental and other agents are causing adverse effects on reproductive function in humans are real, although the risk is not necessarily well characterized. The range of concerns for the types of effect that agents might have on reproduction span the full range of reproductive events....
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.3109/03602539608993992
更新日期：1996-02-01 00:00:00
abstract：:Like any other drugs, antiallergic medications can be associated with large inter- and intraindividual variability in their disposition. The best-documented examples belong to the H1 antihistamines. Variable drugs are more likely to show unpredictable therapeutic response with both increased risks of side effects and ...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.1080/10837450902891485
更新日期：2009-01-01 00:00:00
abstract：:Human tumors arise from multiple genetic changes that gradually transform growth-limited cells into highly invasive cells that are unresponsive to growth controls. The genetic evolution of normal cells into cancer cells is largely determined by the fidelity of DNA replication, repair, and division. Cell-cycle arrest i...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.1081/dmr-100102335
更新日期：2000-08-01 00:00:00
abstract：:Glutathione S-transferase P1-1 (GSTP) is one member of the family of GSTs and is ubiquitously expressed in human tissues. The literature is replete with reports of high levels of GSTP linked either with cancer incidence or drug resistance, and yet no entirely cogent explanation for these correlations exists. The catal...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.3109/03602532.2011.552912
更新日期：2011-05-01 00:00:00
abstract：:N-acetyltransferase 1 (NAT1), a polymorphic Phase II enzyme, plays an essential role in metabolizing heterocyclic and aromatic amines, which are implicated in urinary bladder cancer (BCa). This systematic review investigates a possible association between the different NAT1 genetic polymorphisms and BCa risk. Medline,...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,meta分析,评审
doi：10.1080/03602532.2017.1415928
更新日期：2018-05-01 00:00:00
abstract：:At present, the methods and enzymology of the UDP-glucuronosyltransferases (UGTs) lag behind that of the cytochromes P450 (CYPs). About 15 human UGTs have been identified, and knowledge about their regulation, substrate selectivity, and tissue distribution has progressed recently. Alamethicin has been characterized as...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.1081/dmr-120000653
更新日期：2001-08-01 00:00:00
abstract：:Nano-hydroxyapatite (nano-HA) is a material with multiple uses due to its biocompatibility and its resemblance to the nonorganic bone structure. It is used in various dental domains such as implantology, surgery, periodontology, esthetics and prevention. The aim of this study is to provide a wide understanding of nano...
journal_title：Drug metabolism reviews
pub_type： 杂志文章
doi：10.1080/03602532.2020.1758713
更新日期：2020-05-01 00:00:00
abstract：:The mitochondrial amidoxime-reducing component (mARC) is a recently discovered molybdenum-containing enzyme in mammalians. Upon reconstitution with the electron transport proteins, cytochrome b(5) and its reductase, this molybdenum enzyme is capable of reducing N-hydroxylated compounds. It was named mARC because the N...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.3109/03602532.2011.608682
更新日期：2011-11-01 00:00:00
abstract：:The cannabinoid receptor 1 (CB1) is a G protein-coupled receptor (GPCR) that is located primarily in the central nervous system. CB1 is a therapeutic target which may impact pathways to mediate pain, neurodegenerative disorders, hunger, and drug-seeking behavior. Despite these benefits, development of orthosteric ther...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.1080/03602532.2018.1428342
更新日期：2018-02-01 00:00:00
abstract：:Traditional Chinese medicine (TCM) has a long history of medical use in China and is still used worldwide. Unexpected herb-drug interactions (HDIs) may lead to adverse drug reactions or loss of therapeutic efficacy of the victim drug. Here, based on searches of Medline, EBSCO, Science Direct and Web of Science using v...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.3109/03602532.2015.1124888
更新日期：2016-01-01 00:00:00
