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Drug Metabolism and Disposition: the Biological Fate of Chemicals

Yuki Yamasaki, Kaoru Kobayashi, Fuka Okuya, Naoyo Kajitani, Kanako Kazuki, Satoshi Abe, Shoko Takehara, Shingo Ito, Seiryo Ogata, Tatsuki Uemura, Sumio Ohtsuki, Genki Minegishi, Hidetaka Akita, Kan Chiba, Mitsuo Oshimura, Yasuhiro Kazuki
P-glycoprotein (P-gp), encoded by the MDR1 gene in humans and by the Mdr1a/1b genes in rodents, is expressed in numerous tissues and plays as an efflux pump to limit the distribution and absorption of many drugs. Owing to species differences of P-gp between humans and rodents, it is difficult to predict the impact of P-gp on pharmacokinetics and tissue distribution of P-gp substrates in humans from results of animal experiments. Therefore, we generated a novel P-gp humanized mouse model by using a mouse artificial chromosome (MAC) vector [designated human MDR1-MAC (hMDR1-MAC) mice]...
May 18, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Stanislav Yanev, Tsveta Stoyanova, Violeta Valcheva, Paul R Ortiz De Montellano
Ethionamide (ETH) plays a central role in the treatment of tuberculosis in patients resistant to the first-line drugs. The ETH, thioamide, and thiourea class of antituberculosis agents are pro-drugs that are oxidatively converted to their active S-oxides by the flavin monooxygenase EtaA of M. tuberculosis, thus initiating the chain of reactions that result in inhibition of mycolic acid biosynthesis and cell lysis. As part of a search for new lead candidates, we report here that several xanthates are oxidized by purified EtaA to S-oxide metabolites (perxanthates) that are implicated in the antimycobacterial activity of these compounds...
May 18, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Hong Shen, Lisa Christopher, Yurong Lai, Jiachang Gong, Hamza Kandoussi, Samira Garonzik, Vidya Perera, Tushar Garimella, W Griffith Humphreys
In a recent study, limited to South Asian Indian subjects (n=12), coproporphyrin I and III (CPI and CPIII) demonstrated properties appropriate for an OATP1B endogenous probe (Lai et al., 2016). The current studies were conducted in healthy volunteers of mixed ethnicities, including black, white, and Hispanic subjects to better understand the utility of these biomarkers in broader populations. After oral administration with 600 mg rifampin, AUC(0-24h) values were 2.8-, 3.7- and 3.6-fold higher than predose levels for CPI and 2...
May 18, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Xu Mao, Zi Xia Hu, Qian Wang, Na Zhang, Shen Zhi Zhou, Ying Peng, Jiang Zheng
Nitidine chloride (NC) is a benzophenanthridine alkaloid isolated from the roots of Zanthoxylum nitidum (Roxb.) DC, a widely used traditional herbal medicine. NC has been reported to reveal multiple pharmacologic properties. The inhibitory effects of NC on human cytochrome P450 enzymes were investigated in the present study. We found that NC caused time- and concentration-dependent inhibition of CYP2D6, and more than 50% of CYP2D6 activity was suppressed after 15 min incubation with NC at 100 μM in the primary incubation mixtures, with KI of 4...
May 17, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Cindy Yanfei Li, Joseph L Dempsey, Dongfang Wang, SooWan Lee, Kris M Weigel, Qiang Fei, Deepak Kumar Bhatt, Bhagwat Prasad, Daniel Raftery, Haiwei Gu, Julia Yue Cui
Polybrominated diphenyl ethers (PBDEs) are persistent environmental contaminants with well-characterized toxicities in host organs. Gut microbiome is increasingly recognized as an important regulator of xenobiotic biotransformation; however, little is known about its interactions with PBDEs. Primary bile acids (BAs) are metabolized by the gut microbiome into more lipophilic secondary BAs that may be absorbed and interact with certain host receptors. The goal of this study was to test our hypothesis that PBDEs cause dysbiosis and aberrant regulation of BA homeostasis...
May 16, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Eiji Hishinuma, Yoko Narita, Sakae Saito, Masamitsu Maekawa, Fumika Akai, Yuya Nakanishi, Jun Yasuda, Masao Nagasaki, Masayuki Yamamoto, Hiroaki Yamaguchi, Nariyasu Mano, Noriyasu Hirasawa, Masahiro Hiratsuka
Dihydropyrimidine dehydrogenase (DPD, EC, encoded by the DPYD gene, is the rate-limiting enzyme in the degradation pathway of endogenous pyrimidine and fluoropyrimidine drugs such as 5-fluorouracil (5-FU). DPD catalyzes the reduction of uracil, thymine, and 5-FU. In Caucasians, DPYD mutations, including DPYD*2A, DPYD*13, c.2846A>T, and 1129-5923C>G/hapB3, are known to contribute to interindividual variations in the toxicity of 5-FU. However, none of these DPYD polymorphisms have been identified in the Asian population...
May 16, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Bryan Mackowiak, Jessica Hodge, Sydney Stern, Hongbing Wang
Over the past 20 years, the ability of the xenobiotic receptors to coordinate an array of drug-metabolizing enzymes and transporters in response to endogenous and exogenous stimuli has been extensively characterized and well documented. The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) are the xenobiotic receptors that have received the most attention, as they regulate the expression of numerous proteins important to drug metabolism and clearance and formulate a central defensive mechanism to protect the body against xenobiotic challenges...
May 14, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Mayukh Banerjee, Gurnit Kaur, Brayden D Whitlock, Michael W Carew, X Chris Le, Elaine M Leslie
The ATP-binding cassette (ABC) transporter Multidrug Resistance Protein 1 (MRP1/ABCC1) is known to protect cells from the proven human carcinogen arsenic through the cellular efflux of arsenic triglutathione [As(GS)3], and the diglutathione conjugate of the highly toxic monomethylarsonous acid (MMAIII) [MMA(GS)2]. Previously, differences in MRP1 phosphorylation (at Y920/S921) and N-glycosylation (at N19/N23) were associated with marked differences in As(GS)3 transport kinetics between HEK293 and HeLa cell lines...
May 11, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Shinji Yamazaki, Cho-Ming Loi, Emi Kimoto, Chester Costales, Manthena V Varma
Bosutinib is an orally available Src/Abl tyrosine kinase inhibitor indicated for the treatment of patients with Ph+ chronic myelogenous leukemia at a clinically recommended dose of 500 mg once daily. Clinical results indicated that increases in bosutinib oral exposures were supra-proportional at the lower doses (50 to 200 mg) and approximately dose-proportional at the higher doses (200 to 600 mg). Bosutinib is a substrate of CYP3A4 and P-glycoprotein and exhibits pH-dependent solubility with moderate intestinal permeability...
May 8, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Mary F Paine, Danny D Shen, Jeannine S McCune
Sales of botanical dietary supplements and other purported medicinal natural products (NPs) have escalated over the past ~25 years, increasing the potential for NPs to precipitate clinically significant pharmacokinetic interactions with United States Food and Drug Administration (FDA)-approved medications (NP-drug interactions or NPDIs). Published NPDI studies to date often lack consistency in design, implementation, and documentation, which present difficulties in assessing the clinical significance of the results...
May 7, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Faraz Kazmi, Phyllis Yerino, Chase McCoy, Andrew Parkinson, David B Buckley, Brian W Ogilvie
Oligonucleotides represent an expanding class of pharmacotherapeutics in development for various indications. Typically, oligonucleotides are developed with phosphorothioate linkages for the improvement of biological stability; however limited data are available on the potential of these molecules to cause drug-drug interactions (DDIs). In the present study, two non therapeutic oligonucleotides with either phosphodiester (PD-GP and PD-Ac) or phosphorothioate (PT-GP and PT-Ac) linkages were evaluated in vitro for their potential to inhibit P450s and UGTs in both human liver microsomes (HLM) and cryopreserved human hepatocytes (CHH) and to inhibit select transporters in expression systems...
May 7, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Ulrike Glaenzel, Yi Jin, Robert Nufer, Wenkui Li, Kirsten Schroer, Sylvie Adam-Stitah, Sjoerd Peter van Marle, Eric Legangneux, Hubert Borell, Alexander David James, Axel Meissner, Gian Camenisch, Anne Gardin
Siponimod, a next generation selective sphingosine-1-phosphate receptor modulator, is currently being investigated for the treatment of secondary progressive multiple sclerosis. We investigated the absorption, distribution, metabolism and excretion of a single oral dose of [14 C]siponimod 10 mg in four healthy male subjects. Mass balance, blood and plasma radioactivity, and plasma siponimod concentrations were measured. Metabolite profiles were determined in plasma, urine and feces. Metabolite structures were elucidated using mass spectrometry and comparison with reference compounds...
May 7, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Emily J Johnson, Vanessa Gonzalez-Perez, Dan-Dan Tian, Yvonne S Lin, Jashvant D Unadkat, Allan E Rettie, Danny D Shen, Jeannine S McCune, Mary F Paine
Pharmacokinetic interactions between natural products (NPs) and conventional medications (prescription and non-prescription) are a longstanding but understudied problem in contemporary pharmacotherapy. Consequently, there are no established methods for selecting and prioritizing commercially available NPs to evaluate as precipitants of NP-drug interactions (NPDIs). As such, NPDI discovery remains largely a retrospective, bedside-to-bench process. This Recommended Approach, developed by the Center of Excellence for Natural Product Drug Interaction Research (NaPDI Center), describes a systematic method for selecting NPs to evaluate as precipitants of potential clinically significant pharmacokinetic NPDIs...
May 7, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Tom de Bruyn, Ayse Ufuk, Carina Cantrill, Rachel E Kosa, Yi-An Bi, Mark Niosi, Sweta Modi, A David Rodrigues, Larry M Tremaine, Manthena Vs Varma, Aleksandra Galetin, J Brian Houston
This work explores the utility of the cynomolgus monkey as a preclinical model to predict hepatic uptake clearance mediated by organic anion transporting polypeptide (OATP) transporters. Nine OATP substrates (rosuvastatin, pravastatin, repaglinide, fexofenadine, cerivastatin, telmisartan, pitavastatin, bosentan and valsartan) were investigated in plated cynomolgus monkey and human hepatocytes. Total uptake clearance and passive diffusion were measured in vitro from initial rates in the absence and presence of the OATP inhibitor rifamycin SV, respectively...
May 2, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Yoshiaki Yao, Kota Toshimoto, Soo-Jin Kim, Takashi Yoshikado, Yuichi Sugiyama
Cerivastatin (CER) was withdrawn from the world market because of lethal rhabdomyolysis. Coadministrations of CER and cyclosporine A (CsA) or gemfibrozil (GEM) have been reported to increase the CER blood concentration. CsA is an inhibitor of OATP1B1 and CYP3A4, and GEM and its glucuronide (GEM-glu) inhibit OATP1B1 and CYP2C8. The purpose of this study was to describe the transporter-/enzymemediated drug-drug interactions (DDIs) of CER with CsA or GEM based on unified physiologically based pharmacokinetic (PBPK) models and to investigate whether the DDIs can be quantitatively analyzed by a bottom-up approach...
April 30, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Matthew R Durk, Gauri Deshmukh, Nicole Valle, Xiao Ding, Bianca M Liederer, Xingrong Liu
Microdialysis is a powerful technique allowing for real-time measurement of unbound drug concentrations in brain interstitial fluid (ISF) in conscious animals. Use of microdialysis in drug discovery is limited by high resource requirement and low throughput, but this may be improved by cassette dosing. Administering multiple compounds intravenously (IV) of diverse physiochemical properties, it is often very challenging and time-consuming to identify a vehicle that can dissolve all the compounds. To overcome this limitation, the present study explores the possibility of administering a cassette dose of 9 diverse compounds (carbamazepine, citalopram, desmethylclozapine, diphenhydramine, gabapentin, metoclopramide, naltrexone, quinidine, and risperidone) in suspension, rather than in solution, by intraperitoneal and subcutaneous routes, and determining if this is a viable option for assessing BBB penetration in microdialysis studies...
April 26, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Bhagwat Prasad, Deepak Kumar Bhatt, Katherine Johnson, Revathi Chapa, Xiaoyan Chu, Laurent Salphati, Guangqing Xiao, Caroline Lee, Cornelis Eca Hop, Anita Mathias, Yurong Lai, Mingxiang Liao, W Griffith Humphreys, Sean C Kumer, Jashvant D Unadkat
To predict the impact of liver cirrhosis on hepatic drug clearance using physiologically based pharmacokinetic (PBPK) modeling, we compared the protein abundance of various Phase I and Phase II drug metabolizing enzymes (DMEs) in S9 fractions of alcoholic (n=27) or hepatitis C (HCV, n=30) cirrhotic vs. non-cirrhotic (control) livers (n=25). The S9 total protein content was significantly lower in alcoholic or HCV cirrhotic vs. control livers (i.e., 38.3 ± 8.3, 32.3 ± 12.8 vs. 51.1 ± 20.7 mg/g liver, respectively)...
April 25, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Aarti Sawant-Basak, R Scott Obach, Angela C Doran, Peter Lockwood, Klaas Schildknegt, Hongying Gao, Jessica Mancuso, Susanna Tse, Tom Comery
SAM-760, (2-methyl-1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-benzo[d]imidazole), a 5HT6 antagonist, was investigated in humans for the treatment of Alzheimer's dementia. In liver microsomes and recombinant CYP450 isozymes, SAM-760 was predominantly metabolized by CYP3A (~85%). Based on these observations and an expectation of 5-fold magnitude of interaction with moderate to strong CYP3A inhibitors, a clinical DDI study was performed. In presence of ketoconazole, mean Cmax and AUC0-inf of SAM-760 showed only a modest increase by 30% and 38%, respectively...
April 25, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Kimberly L Garrison, Polina German, Erik Mogalian, Anita Mathias
Several safe and highly-effective directly-acting antiviral drugs for chronic hepatitis C virus (HCV) have been developed and greatly increase the number of treatment options available to successfully treat HCV infection. However, as treatment regimens contain at least two drugs (e.g., sofosbuvir with daclatasvir, simeprevir, ledipasvir, or velpatasvir; elbasvir and grazoprevir) and up to five drugs (ombitasvir/paritaprevir/ritonavir+dasabuvir+ribavirin), the potential for drug-drug interactions (DDI) becomes an important consideration for HCV-infected individuals with comorbidities that require concomitant medications, such as HIV/HCV co-infection or immunosuppression following liver transplantation...
April 25, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Meetal Satishkumar Solanki, Amy Pointon, Barry C Jones, Karl E Herbert
Drug-induced cardiotoxicity may be modulated by endogenous arachidonic acid (AA) derived metabolites known as epoxyeicosatrienoic acids (EETs) synthesised by cytochrome P450 2J2 (CYP2J2). The biological effects of EETs including its protective effects on inflammation and vasodilation are diverse due, in part, to their ability to act on a variety of cell types. In addition, CYP2J2 metabolises both exogenous and endogenous substrates and is involved in phase I metabolism of a variety of structurally diverse compounds including some antihistamines, anti-cancer agents and immunosuppressants...
April 25, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
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