Abstract：
:The high rate of attrition during drug development and its associated high research and development (R&D) cost have put pressure on pharmaceutical companies to ensure that candidate drugs going to clinical testing have the appropriate quality such that the biological hypothesis could be evaluated. To help achieve this ambition, drug metabolism and pharmacokinetic (DMPK) science and increasing investment have been deployed earlier in the R&D process. To gain maximum return on investment, it is essential that DMPK concepts are both appropriately integrated into the compound design process and that compound selection is focused on accurate prediction of likely outcomes in patients. This article describes key principles that underpin the contribution of DMPK science for small-molecule research based on 15 years of discovery support in a major pharmaceutical company. It does not aim to describe the breadth and depth of DMPK science, but more the practical application for decision making in real-world situations.
journal_name
Drug Metab Revjournal_title
Drug metabolism reviewsauthors
Ballard P,Brassil P,Bui KH,Dolgos H,Petersson C,Tunek A,Webborn PJdoi
10.3109/03602532.2012.691099subject
Has Abstractpub_date
2012-08-01 00:00:00pages
224-52issue
3eissn
0360-2532issn
1097-9883journal_volume
44pub_type
杂志文章,评审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：:Hepatotoxicity is a serious problem during drug development and for the use of many established drugs. For example, acetaminophen overdose is currently the most frequent cause of acute liver failure in the United States and Great Britain. Evaluation of the mechanisms of drug-induced liver injury indicates that mitocho...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.3109/03602532.2011.602688
更新日期：2012-02-01 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：: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：:Much is known about the distal DNA damage repair response. In particular, many of the enzymes and auxiliary proteins that participate in DNA repair have been characterized. In addition, knowledge of signaling pathways activated in response to DNA damage is increasing. In contrast, comparatively less is known of DNA da...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.1080/03602530600959649
更新日期：2006-01-01 00:00:00
abstract：:The cytochrome P450 (P450) field came out of interest in the metabolism of drugs, carcinogens, and steroids, which remain major focal points. Over the years we have come to understand the P450 system components, the multiplicity of P450s, and many aspects of the regulation of the genes and also the catalytic mechanism...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.1081/dmr-120033996
更新日期：2004-05-01 00:00:00
abstract：:The present paper has discussed available test systems for determination of the response of G-6-PD-deficient human erythrocytes to environmental agents. The limitations and advantages of each model have been examined, and the results of research using each model have been presented. The future development of suitable ...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.3109/03602538608998292
更新日期：1986-01-01 00:00:00
abstract：:For patients undergoing cardiopulmonary bypass (CPB) during cardiac surgery, there are well-documented changes in the pharmacokinetics (PK) of commonly administered drugs. Although multiple factors potentially underpin these changes, there has been scant research attention on the impact of CPB to alter the activities ...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.1080/03602532.2017.1417423
更新日期：2018-05-01 00:00:00
abstract：:Herbert Remmer was a pioneer in the study of the phenomenon of enzyme induction. He was also a leading figure, if not the foremost, in the development of the discipline of toxicology in Germany during his tenure as Professor of Toxicology at the University of Tübingen. Included here are some brief thoughts about where...
journal_title：Drug metabolism reviews
pub_type： 传,历史文章,杂志文章
doi：10.1081/dmr-200033409
更新日期：2004-10-01 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：: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
abstract：:The multiple functions of NAD(P)H:quinone oxidoreductase 1 (NQO1, DT-diaphorase) in the cell are reviewed. NQO1 has long been viewed as a chemoprotective enzyme involved in cellular defense against the electrophilic and oxidizing metabolites of xenobiotic quinones. It also participates in reduction of endogenous quino...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.1081/dmr-200033465
更新日期：2004-10-01 00:00:00
abstract：:In this paper, we evaluate methodologies and null mouse models used to study drug transporter function in vitro and in vivo. P-glycoprotein and MRP null mice have been used to examine many aspects of xenobiotic distribution and bioavailability. Their advantage over conventional models is that they allow the exclusion ...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.1080/03602530802605040
更新日期：2009-01-01 00:00:00
abstract：:Cytochrome P450 (CYP) 2D6 is one of the most important enzymes involved in the metabolism of drugs. Multiple, clinically relevant, genetic variants of this gene have been identified and, among them, a gene deletion as well as multiplications of the gene. These large structural mutations in CYP2D6 occur at a relatively...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.1080/03602530600952206
更新日期：2007-01-01 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 cytochrome P450 (CYP) 3A subfamily members (mainly CYP3A4 and CYP3A5) mediate the metabolism of approximately half all marketed drugs and thus play a critical role in the drug metabolism. A huge number of studies on CYP3A-mediated drug metabolism in humans have demonstrated that CYP3A activity exhibits marked et...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.1080/03602530701690374
更新日期：2007-01-01 00:00:00
abstract：:Atrial fibrillation (AF) is the most common arrhythmia in clinical practice and is associated with decreased quality of life, and increased mortality and morbidity from stroke and thromboembolism. The underlying mechanisms involved in the development of AF have yet to be fully elucidated. However, once initiated, AF t...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.3109/03602532.2015.1077858
更新日期：2015-08-01 00:00:00
abstract：:Cyclindole was extensively metabolized and eliminated primarily via the kidneys from most laboratory animals and man. Only in the dog was cyclindole a major urinary component. Cyclindole was metabolized by N-demethylation and/or hydroxylation. In studies utilizing radiolabeled drug, the primary urinary component was p...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.3109/03602538008994027
更新日期：1980-01-01 00:00:00
abstract：:Drug transporters and drug metabolism enzymes govern drug absorption, distribution, metabolism and elimination. Many literature works presenting important aspects related to stereochemistry of drug metabolism are available. However, there is very little literature on stereoselectivity of chiral drug transport and enan...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.3109/03602532.2014.887094
更新日期：2014-08-01 00:00:00
abstract：:Bupropion is an atypical antidepressant of the aminoketone group, structurally related to cathinone, associated with a wide interindividual variability. An extensive pharmacokinetic and pharmacodynamic review of bupropion was performed, also focusing on chemical, pharmacological, toxicological, clinical and forensic a...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.1080/03602532.2019.1620763
更新日期：2019-08-01 00:00:00
abstract：:Acetaminophen (APAP, paracetamol, N-acetyl-p-aminophenol) is a widely used analgesic that is safe at therapeutic doses but is a major cause of acute liver failure (ALF) following overdose. APAP-induced hepatotoxicity is related to the formation of an electrophilic reactive metabolite, N-acetyl-p-benzoquinone imine (NA...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.3109/03602532.2014.982865
更新日期：2015-02-01 00:00:00
abstract：:Cytochrome P450-based cancer gene therapy is a novel prodrug activation strategy for cancer treatment that has substantial potential for improving the safety and efficacy of cancer chemotherapeutics. The primary goal of this strategy is to selectively increase tumor cell exposure to cytotoxic drug metabolites generate...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.1081/dmr-100101933
更新日期：1999-05-01 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：: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：: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：: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, indica...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.1080/03602532.2020.1726944
更新日期：2020-05-01 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 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：:Chemicals that cause toxicity though a direct mechanism, such as acetaminophen, covalently bind to a select group of proteins prior to the development of toxicity, and these proteins may be important in the initiation of the events that lead to the hepatotoxicity. Disruption of the cell is measured by release of intra...
journal_title：Drug metabolism reviews
pub_type： 杂志文章,评审
doi：10.3109/03602539709037572
更新日期：1997-02-01 00:00:00
