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Current Drug Metabolism

Qinghua Wu, Kamil Kuca
Cyclosporine A (CsA) is widely used for organ transplantation and autoimmune disorders. However, CsA nephrotoxicity is a serious side effect that limits the clinical use of CsA. Notably, the metabolism of CsA has a close relationship with this disease in renal-transplant patients. The major metabolic pathways of CsA in humans are hydroxylation (AM1 and AM9) and N-demethylation (AM4N). Normally, these metabolites are relatively less toxic than CsA. However, the metabolism of CsA in the kidneys is much weaker than that in the liver, which explains why CsA is so toxic to the kidneys...
October 31, 2018: Current Drug Metabolism
Wei Chen, Pengmian Feng, Tao Liu, Dianchuan Jin
Background: As molecular chaperones, heat shock proteins (HSPs) not only play key roles in protein folding and maintaining protein stabilities, but also linked with multiple kinds of diseases. Therefore, HSPs have been regarded as the focus of drug design. Since HSPs from different families play distinct functions, accurately classifying the families of HSPs is the key step to clearly understand their biological functions. In contrast to labor-intensive and cost-ineffective experimental methods, accurately computational classification of HSP families has emerged to be an alternative approach...
October 30, 2018: Current Drug Metabolism
Aisling Mangan, Carel Le Roux, Nana Gletsu Miller, Neil Docherty
BACKGROUND: Nutritional deficiencies are common following Roux-en-Y gastric bypass (RYGB). Aetiology is diverse; including unresolved preoperative deficiency, post-operative malabsorption and reduced food intake. Iron and calcium/vitamin D deficiency are particularly troublesome following RYGB. Currently, treatment strategies recommend the prescription of complex regimens of supplements with high doses for those who become deficient. Meanwhile, debate exists regarding the absorption capacity of these post-operatively and their efficacy in treating deficiency...
October 26, 2018: Current Drug Metabolism
Aditi Shah, Souvik Sen Gupta
Leishmaniasis is a dreaded disease caused by protozoan parasites belonging to the genus Leishmania which results in significant morbidity and mortality worldwide. There are no vaccines available currently for the treatment of Leishmaniasis and chemotherapy still remains the mainstay for anti-leishmanial therapeutics. However, toxicity, reduced bioavailability, high cost and chemoresistance are the principal problems which limit the use of the available drugs. In this context, anti-leishmanial nanotherapeutics may show the way for effective treatment of this dreaded disease...
October 22, 2018: Current Drug Metabolism
Juanhong Zhang, Junmin Zhang, Rong Wang, Zhengping Jia
BACKGROUND: Modern features of drug development such as low permeability, low solubility, and improved release affect the interplay of the gut microbiota and drug metabolism. In recent years, studies have established the impact of plateau hypoxia on gut microbiota, where drug use by plateau populations is affected by hypoxia-induced changes in intestinal microflora-mediated drug metabolism. METHODS: In this review, we summarized the effects of gut microbiota on drug metabolism, and of plateau hypoxia on the intestinal flora, with the aim of providing guidance for the rational use of drugs in high-altitude populations...
October 19, 2018: Current Drug Metabolism
Yi Xiong, Yanhua Qiao, Daisuke Kihara, Hui-Yuan Zhang, Xiaolei Zhu, Dong-Qing Wei
BACKGROUND: Determination or prediction of the absorption, distribution, metabolism, and excretion (ADME) properties of drug candidates and drug-induced toxicity play crucial roles in drug discovery and development. Metabolism is one of the most complicated pharmacokinetic properties to be understood and predicted. However, experimental determination of the substrate binding, selectivity, sites and rates of metabolism is time- and recourse- consuming. In the phase I metabolism of foreign compounds (i...
October 18, 2018: Current Drug Metabolism
Zhongyan Li, Qingqing Miao, Fugang Yan, Yang Meng, Peng Zhou
BACKGROUND: Protein-peptide recognition plays an essential role in the orchestration and regulation of cell signaling networks, which is estimated to be responsible for up to 40% of biological interaction events in the human interactome and has recently been recognized as a new and attractive druggable target for drug development and disease intervention. METHODS: We present a systematic review on the application of machine learning techniques in the quantitative modeling and prediction of protein-peptide binding affinity, particularly focusing on its implications for therapeutic peptide design...
October 12, 2018: Current Drug Metabolism
Delai Xu, Cujin Su, Jie Pan
Dabigatran etexilate (DE) was approved by the FDA in 2010 to reduce the risk of stroke and systemic embolism in adults with non-valvular atrial fibrillation (NVAF). Compared with warfarin, a traditional anticoagulant drug, DE exhibits a shorter half-life, improved dose-effect relationship, fewer food and drug interactions, and can be taken orally without monitoring the conventional coagulation index. DE can also prevent or reduce the severity of adverse events, such as attenuated drug efficacy or bleeding. It is convenient for patients to take DE due to low levels of individual variation...
October 11, 2018: Current Drug Metabolism
Huan-Huan Wei, Wuritu Yang, Hua Tang, Hao Lin
BACKGROUND: Cell-penetrating peptides (CPPs) are important short peptides that facilitate cellular intake or uptake of various molecules. CPPs can transport drug molecules through the plasma membrane and send these molecules to different cellular organelles. Thus, CPP identification and related mechanisms have been extensively explored. In order to reveal the penetration mechanisms of a large number of CPPs, it is necessary to develop convenient and fast methods for CPPs identification...
October 10, 2018: Current Drug Metabolism
Shotaro Uehara, Toru Oshio, Kazuyuki Nakanishi, Etsuko Tomioka, Miyu Suzuki, Takashi Inoue, Yasuhiro Uno, Erika Sasaki, Hiroshi Yamazaki
BACKGROUND: Common marmosets (Callithrix jacchus) are potentially useful nonhuman primate models for preclinical studies. Information for major drug-metabolizing cytochrome P450 (P450) enzymes is now available that supports the use of this primate species as an animal model for drug development. Here, we collect and provide an overview of information on the activities of common marmoset liver and intestine microsomes with respect to 28 typical human P450 probe oxidations. RESULTS: Marmoset P450 2D6/8-dependent R-metoprolol O-demethylation activities in liver microsomes were significantly correlated with those of midazolam 1'- and 4-hydroxylations, testosterone 6β-hydroxylation, and progesterone 6β-hydroxylation, which are probe reactions for marmoset P450 3A4/5/90...
October 3, 2018: Current Drug Metabolism
Yumiko Akamine, Norio Yasui-Furukori, Tsukasa Uno
Background: Recent US Food and Drug Administration (FDA) draft guidance on pharmacokinetic drug-drug interactions (DDIs) has highlighted the clinical importance of ABC transporters B1 or P-glycoprotein (P-gp), hepatic organic anion-transporting polypeptide transporters and breast cancer resistant protein because of their broad substrate specificity and the potential to be involved in DDIs. This guidance has indicated that digoxin, dabigatran etexilate and fexofenadine are P-gp substrate drugs and has defined P-gp inhibitors as those that increase the AUC of digoxin by ≧1...
October 3, 2018: Current Drug Metabolism
Francesco Paolo Busardo, Massimo Gottardi, Anastasio Tini, Adele Minutillo, Enrico Marinelli, Simona Zaami
BACKGROUND: Recently, gamma-hydroxybutyrate (GHB) consumption in recreational setting shas been replaced by that of its prodrug gamma-butyrolactone (GBL), cheaper and easier to obtain due to several legal industrial applications. OBJECTIVE: The aim of the present paper was to report the most authoritative literature on the pharmacology and toxicology of GBL, dependence and abuse potential and the related public health issues together with the results of the analyses of several illicit liquid preparations containing GHB/GBL generally sold as "G"...
September 24, 2018: Current Drug Metabolism
Mengjie Yang, Gui Huan, Mei Wang
Single nucleotide polymorphisms (SNPs) are the most common variants in many genes, which are also promising markers in relation to drug responses in pharmacogenomics studies. Tacrolimus is a primary immunosuppressant used for the prevention of organ rejection in pediatric organ transplantation. Tacrolimus, transported out of cells via P-glycoprotein (ABCB1), is also a metabolic substrate for cytochrome P450 (CYP) 3A enzymes, especially the CYP3A4 and the CYP3A5. The SNP of these genes have been studied extensively in adult population, but there is no systematic review in children...
September 24, 2018: Current Drug Metabolism
Nitin Gupta, Divya Bharti Rai, Ashok Kumar Jangid, Hitesh Kulhari
BACKGROUND: In last few years, the use of modified carbon nanomaterials (CNMs) for theranostics (therapeutic and diagnosis) applications is a new and rapidly growing area in pharmacy and medical fields. Owing to this, their unique physical and chemical properties like high stability, high drug loading with high surface to volume ratio, low toxicity are mainly responsible to be considered those as smart nanomaterials. OBJECTIVE: This review describes the different sizes, shapes, and dimensions of carbon-based nanocarriers including 0-D fullerene, 1-D CNTs, and 2-D graphene and graphene oxide and their surface modification with different biocompatible and biodegradable molecules via covalent or non-covalent functionalization...
September 24, 2018: Current Drug Metabolism
Yang Hu, Tianyi Zhao, Ningyi Zhang, Ying Zhang, Liang Cheng
From a therapeutic viewpoint, understanding how drugs bind and regulate the functions of their target proteins to protect against disease is crucial. The identification of drug targets plays a significant role in drug discovery and in studying the mechanisms of diseases. The development of methods to identify drug targets has become a popular issue in this field of research. Originally, scientists used biological experiments to identify drug targets. However, recently, an increasing number of scientists use computational methods to identify drug targets...
September 24, 2018: Current Drug Metabolism
Ke Chen, Jinwei Zhong, Lin Hu, Ruliu Li, Qun Duc, Jiazhong Cai, Yanwu Li, Yong Gao, Xiaona Cui, Xiaoying Yang, Xiaojie Wu, Lu Yao, Juji Dai, Yan Wang, Haiyong Jin
PXR (pregnane X receptor) and CAR (constitutive androstane receptor) are termed as xenobiotic receptors, which are known as core factors in the regulation of the transcription of metabolic enzymes and drug transporters. However, accumulating evidence has shown that PXR and CAR exert their effects on energy metabolism through the regulation of gluconeogenesis, lipogenesis, and β-oxidation. Therefore, PXR and CAR may become new therapeutic targets for metabolic syndrome, including obesity and diabetes. In this review, we will summarize recent advances to show how xenobiotic receptors regulate energy metabolism...
September 18, 2018: Current Drug Metabolism
Vivek K Chaturvedi, Anshuman Singh, Vinay K Singh, M P Singh
Background- Nanotechnology is gaining significant attention worldwide for cancer treatment. Nano-biotechnology encourages the combination of diagnostics with therapeutics, which is a vital component of a customized way to deal with the malignancy. Nanoparticles are being used as Nanomedicine which participates in diagnosis and treatment of various diseases including cancer. The unique characteristic of Nanomedicine i.e. their high surface to volume ratio enables them to tie, absorb, and convey small biomolecule like DNA, RNA, drugs, proteins, and other molecules to the targeted site and thus enhances the efficacy of therapeutic agents...
September 18, 2018: Current Drug Metabolism
Anil K Sharma, Var Ruchi Sharma, Girish K Gupta, Ghulam Md Ashraf, Mohammad A Kamal
BACKGROUND: Advanced glycation end products (AGEs) are basically the end result of glycation of proteins and/or lipids in the presence of sugars. Specific cases of hyperglycemia have been reported with increased propensity of generation of AGEs. Many chronic and deadly diseases such as diabetes, cancer and neurodegenerative disorders have been known to be caused as a result of generation of AGEs. The role of glutathione (GSH) metabolism and its intricate association with AGEs has also been well established in breast cancer prognosis and treatment...
September 11, 2018: Current Drug Metabolism
Nantao Zheng, Kairou Wang, Weihua Zhan, Lei Deng
Virus-host protein interactions play essential roles in viral infection and antiviral defenses. Targeting critical viral-host protein-protein interactions (PPIs) has enormous application prospects for therapeutics. Using experimental methods to evaluate all possible virus-host PPIs takes a great deal of money and time. Recent growth in computational identification of virus-host PPIs provides new opportunities for gaining biological insights, including applications in disease control. We provide an overview of recent computational approaches for studying virus-host PPI interactions...
August 29, 2018: Current Drug Metabolism
Li Di
Carboxylesterases (CES) play a critical role in catalyzing hydrolysis of esters, amides, carbamates and thioesters, and bioconverting prodrugs and soft drugs. Human CES1 is one of the most highly expressed drug metabolizing enzymes in the liver, while human intestine only expresses CES2. The unique tissue distribution of CES enzymes provides great opportunities to design prodrugs or soft drugs for tissue targeting. CES enzymes have moderate to high inter-individual variability and exhibit low to no expression in the fetus, but increase substantially during the first few months of life...
August 20, 2018: Current Drug Metabolism
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