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Drug Metabolism Letters

Siva Prasad Putluru, Murali Krishna Matta, Deepak Ahire, Murali Subramanian, Michael Sinz, Sandhya Mandlekar
Bilirubin is a toxic waste product of metabolism, eliminated mainly through UGT1A1 mediated conjugation to mono- and di-glucuronides. Due to the potentially low Km value of bilirubin glucuronidation, the quantitative sensitivity obtained with most UV/visible light detection methods are not sufficient to accurately calculate UGT1A1 enzyme kinetics and inhibition properties of new chemical entities at low bilirubin concentrations. In addition, bilirubin, as well as its metabolites, are unstable during sample preparation and bioanalysis...
November 24, 2016: Drug Metabolism Letters
Norie Murayama, Makiko Shimizu, Kenta KObayashi, Izumi KIshimoto, Hiroshi Yamazaki
BACKGROUND: A simple method of genotyping and phenotyping cytochrome P450 2A6 (CYP2A6) was previously reported using individual blood samples and urinary caffeine metabolite ratios of 1,7-dimethyluric acid (17U) to 1-methylxanthine (1X). OBJECTIVE: Blood spotted onto storage cards and salivary caffeine metabolites were analyzed in 27 healthy non-smoking Japanese volunteers with no prior abstention from dietary caffeine intake. METHODS: 1,7-Dimethylxanthine (17X), 17U, 1X, and caffeine levels in spot saliva samples were determined in Japanese non-smokers by high-performance liquid chromatography under normal dietary caffeine consumption...
November 14, 2016: Drug Metabolism Letters
Shotaro Uehara, Yasuhiro Uno, Takako Suzuki, Takashi Inoue, Masahiro Utoh, Erika Sasaki, Hiroshi Yamazaki
BACKGROUND: Common marmosets (Callithrix jacchus) and cynomolgus monkeys (Macaca fascicularis) are used as non-human primate models in preclinical studies for drug development. OBJECTIVE: The assessment of P450 induction in hepatocytes from marmosets and cynomolgus monkeys was performed using typical P450 inducers. METHODS: Induction of cytochrome P450 1-4 family enzymes was analyzed in two lots of cultured hepatocytes from common marmosets and cynomolgus monkeys after 24-h treatment with typical human P450 inducing agents by real-time reverse transcription-polymerase chain reaction...
November 14, 2016: Drug Metabolism Letters
Richi Nakatake, Takumi Tsuda, Takashi Matsuura, Hirokazu Miki, Hideki Hishikawa, Hideyuki Matsushima, Morihiko Ishizaki, Kosuke Matsui, Masaki Kaibori, Mikio Nishizawa, Tadayoshi Okumura, Masanori Kon
BACKGROUND/AIMS: Genipin is a component of Japanese traditional herbal medicine (Kampo), inchinkoto, and is used for the treatment of various liver injuries. However, there are few scientific evidence for its anti-inflammatory effects and mechanisms. In inflamed liver, proinflammatory cytokines including tumor necrosis factor (TNF)-α and interleukin (IL)-1β stimulate liver cells, followed by the expression of inducible nitric oxide synthase (iNOS). Excessive levels of NO produced by iNOS have been implicated as one of the factors in liver injury...
October 20, 2016: Drug Metabolism Letters
Akira Ogasawara, Yasuhiro Yamada, Nao Torimoto, Naoki Tsuda, Fumika Aohara, Rikiya Ohashi, Hideki Taniguchi
Cytochrome P450 (CYP) enzymes are induced by some therapeutic drugs, leading to interactions reducing drug plasma concentrations. Recently, an assessment of CYP induction using messenger RNA (mRNA) levels has shown advantages over measurement of enzymatic activity; it has a larger dynamic range of induction and enables us to measure the intrinsic induction potential of time-dependent CYP inhibitors. Therefore, we constructed a new evaluation system for CYP induction combining HepaRG cell line with multiplex branched DNA technologies to measure changes in CYP1A2, CYP2B6, and CYP3A4 mRNA expression from a cell-culture plate, and propose new criteria to evaluate induction potency of CYPs for new chemical entities in early drug discoveries...
August 22, 2016: Drug Metabolism Letters
Ahmad Abdulrahman Almeman, R Ismail, Markus Perola
INTRODUCTION: Methadone is accepted as an alternative therapy in opioid use disorders worldwide. Methadone responsiveness , however, is affected by a range of CYP450 enzymes and OPRM1 polymorphisms. OBJECTIVE: This study sought to detect CYP2B6 and OPRM1 variants and their genotypes, as major contributors to inter-variability in methadone responsiveness and methadone dose requirements. METHODS: We carried out a prospective experimental one-phase pharmacogenetic study in four addiction clinics in Malaysia...
August 10, 2016: Drug Metabolism Letters
Rangaraj Narayanan, Matthew Hoffmann, Gondi Kumar
BACKGROUND: Oncology therapy typically involves drug combinations since monotherapy seldom provides the desired outcome. But combination therapy presents the potential for drug-drug interactions (DDIs). Due to the narrow window between therapeutic concentrations and onset of toxicity often observed with oncology therapeutics, managing DDIs with combination therapy in cancer is critical. Physiologically based pharmacokinetic (PBPK) modeling can be effectively used for predicting DDIs and guiding dose-selection, but requires development of PBPK models of cancer drugs...
July 29, 2016: Drug Metabolism Letters
Cuyue Tang, Hong Jin, Sudarshan Kapadnis, Ting Chen, Dooyoung Lee, Andrew McRiner, Andrew Cook, Duane A Burnett, Gerhard Koenig
Three quinuclidine derivatives (FRM-1, FRM-2 and FRM-3) were subject to significant cellular retention as evidenced by low mass recovery in Caco-2 permeation experiments. The mass recovery deteriorated with incubation time and was direction dependent. According to the apparent permeability coefficient calculated with the conventional 'sink' method (P<sub>app,sink</sub>), the efflux ratio (ER) is close to unity for FRM-1, and approximately 2 and 3.5 for FRM 2 and FRM 3. Treatment with bafilomycin A1 (BFA, 100 nM) did not appreciably change the mass recovery for FRM-2, but considerably enhanced it for FRM-1 and FRM-3, leading to an increase in P<sub>app</sub> by 5- and 2-fold with a negligible impact on ER values...
July 25, 2016: Drug Metabolism Letters
Carla Monalizi Vieira, Michel Leandro Campos, Elias Carvalho Padilha, Ivan da Rocha Pitta, Maria do Carmo Alves de Lima, Rosangela Gonçalves Peccinini
LPSF/GQ-02 is a promising benzylidene thiazolidinedione that have demonstrated antidiabetic, antidyslipidemic, anti-atherosclerotic and can also treat non-alcoholic fatty liver disease. Despite all activity studies of the new compound, its pharmacokinetics are not yet described. Concerning that, the aim of this study was to perform the first pharmacokinetic profile. For this purpose a bioanalytical method for the quantitation of 5-(4-Chloro-benzylidene)-3-(4-methyl-benzyl)-thiazolidine-2,4-dione (LPSF/GQ-02) was developed and validated...
July 25, 2016: Drug Metabolism Letters
Rangaraj Narayanan, Lisa Liu, Matthew Hoffmann, Sekhar Surapaneni
: Chronic kidney disease (CKD) generally impacts clearance of renally eliminated drugs but growing evidence shows that it can influence clearance of hepatically eliminated drugs and a complete mechanistic understanding of this phenomenon is still lacking. CKD leads to accumulation of uremic toxins, including indoxyl-3-sulfate (3-INDS) and indole-3-acetic acid (3-IAA). OBJECTIVE: In this study, we evaluated the potential of 3-INDS and 3-IAA (10, 30 and 100 μM) to induce liver cytochrome P450 (CYP) enzymes CYP1A2, 2B6 and 3A4/5 using cultured primary human hepatocytes following once daily treatment for 3 days...
July 19, 2016: Drug Metabolism Letters
Katsuhisa Kurogi, Ying Hui, Yoichi Sakakibara, Masahito Suiko, Ming-Cheh Liu
The aim of the current study was to identify the human cytosolic sulfotransferases (SULTs) that are capable of sulfating clioquinol and iodoquinol, and to verify the presence of clioquinol/iodoquinol-sulfating activity in human organ homogenates. A systematic analysis revealed that six of the thirteen known human SULTs, SULT1A1 SULT1A2, SULTA3, SULT1B1, SULT1C4, and SULT1E1 showed considerable clioquinol/iodoquinol-sulfating activity. Kinetic parameters of the sulfation of clioquinol and iodoquinol by three SULTs, SULT1A1, SULT1A3, and SULT1C4, that showed the strongest clioquinol/iodoquinol-sulfating activity were determined...
July 19, 2016: Drug Metabolism Letters
Rangaraj Narayanan, Lisa Liu, Matthew Hoffmann, Sekhar Surapaneni
: Chronic kidney disease (CKD) generally impacts clearance of renally eliminated drugs but growing evidence shows that it can influence clearance of hepatically eliminated drugs and a complete mechanistic understanding of this phenomenon is still lacking. CKD leads to accumulation of uremic toxins, including indoxyl-3-sulfate (3-INDS) and indole-3-acetic acid (3-IAA). OBJECTIVE: In this study, we evaluated the potential of 3-INDS and 3-IAA (10, 30 and 100 μM) to induce liver cytochrome P450 (CYP) enzymes CYP1A2, 2B6 and 3A4/5 using cultured primary human hepatocytes following once daily treatment for 3 days...
July 19, 2016: Drug Metabolism Letters
Churdsak Jaikang
Caffeic acid (CAF) and its amide analogues, ethyl 1-(3',4'-dihydroxyphenyl) propen amide (EDPA), phenethyl 1-(3',4'-dihydroxyphenyl) propen amide (PEDPA), phenmethyl 1-(3',4'-dihydroxyphenyl) propen amide (PMDPA) and octyl 1-(3',4'-dihydroxyphenyl) propen amide (ODPA) were investigated for the inhibition of procarcinogen activating enzyme, CYP1A2 and scavenging activity on formation of nitric oxide, superoxide anion, DPPH radical and hydroxyl radical. It was found that they inhibited CYP1A2 enzyme by uncompetitive inhibition...
June 8, 2016: Drug Metabolism Letters
Pollen K Yeung, Shyam Sundar Kolathuru, Remigius U Agu
BACKGROUND: Previous studies have shown that catabolism of adenosine 5'-triphosphate (ATP) in red blood cell (RBC) may be a key factor for cardiovascular protection and maintaining cardiovascular homeostasis. OBJECTIVE: To investigate the effect of cardiovascular injury on adenosine and ATP catabolism in systemic blood using a freely moving rat model in vivo. METHOD: After acclimatized to the experimental environment, Sprague Dawley (SD) rats were each given either isoproterenol (30 mg/kg) or saline (1 mL/kg) by subcutaneous (sc) injection...
June 6, 2016: Drug Metabolism Letters
Vincent Chan, John Mishriky, Jacqueline Balassone, Zenah Bashour, Simranjit Kaur, Vini Raman, Robel Getachew, Narin Osman, Daniel Guidone, Peter J Little
BACKGROUND: Sodium fusidate (fusidic acid) is an antimicrobial agent that is used in the treatment of staphylococcal and streptococcal infections. Several case reports have noted a drug interaction between sodium fusidate and CYP3A4 metabolised statins, leading to statin toxicity. It is unclear whether sodium fusidate has the potential to cause interactions with other cytochrome P450 enzymes. OBJECTIVE: To investigate the effects of sodium fusidate on recombinant cytochrome P450 enzymes (1A2, 2C9, 2C19, 2D6 and 3A4) in-vitro...
June 6, 2016: Drug Metabolism Letters
Suresh K Balani
No abstract text is available yet for this article.
2016: Drug Metabolism Letters
Julius L Apuy, Cathie Xiang, Sarah Franc, Sayee G Hegde, Robert Hubbard, Jingjing Zhao, Mehran F Moghaddam
BACKGROUND: The study of novel sites of metabolism is important in understanding new mechanisms of biotransformation of a particular moiety by metabolic enzymes. This information is valuable in designing metabolically-stable compounds with drug-like properties. It may also provide insights into the existence of active and reactive metabolites. METHODS: We utilized small scale incubations to generate adequate amounts of the metabolite of interest. After purification, LC-MS/MS and Proton Nuclear Magnetic Resonance (1H-NMR) were utilized to unequivocally assign the novel site of glutathione conjugation on the purine ring system...
2016: Drug Metabolism Letters
Hoa Le, Peter W Fan, Susan Wong, Shuguang Ma, James P Driscoll, Cornelis E C A Hop, S Cyrus Khojasteh
BACKGROUND: Tofacitinib is known to generate two metabolites M2 (alcohol) and M4 (acid), which are formed as the result of oxidation and loss of the nitrile [1]. METHOD: Systematic in vitro investigation into generation of M2 and M4 from tofacitinib. RESULTS: In vitro using human liver microsomes, we found a new geminal diol metabolite of tofacitinib (MX) that lost the nitrile. MX was further reduced or oxidized to M2 (alcohol) and M4 (acid), respectively by enzymes such as aldo-keto reductase 1C1, aldehyde oxidase and possibly CYP3A4...
2016: Drug Metabolism Letters
Peter W Fan, Jacob Z Chen, M Allan Jaochico, Hank La, Ning Liu, Teresa Mulder, Robert T Cass, Matthew Durk, Kirsten Messick, Nicole Valle, Shannon Liu, Wendy Lee, James J Crawford, Joachim Rudolf, Lesley J Murray, S Cyrus Khojasteh, Matthew Wright
BACKGROUND: Significant under-prediction of in vivo clearance in rat was observed for a potent p21-activated kinase (PAK1) inhibitor, GNE1. OBJECTIVE: Rate-determining (rapid uptake) and rate-limiting (slow excretion) steps in systemic clearance and elimination of GNE1, respectively, were evaluated to better understand the cause of the in vitro-in vivo (IVIV) disconnect. METHODS: A series of in vivo, ex vivo, and in vitro experiments were carried out: 1) the role of organic cation transporters (Oct or Slc22a) was investigated in transporter knock-out and wild-type animals with or without 1-aminobenzotriazole (ABT) pretreatment; 2) the concentration-dependent hepatic extraction ratio was determined in isolated perfused rat liver; and 3) excreta were collected from both bile duct cannulated and non-cannulated rats after intravenous injection...
2016: Drug Metabolism Letters
Lorraine Thong, John MacSharry, Desmond M Murphy
BACKGROUND: Statins have been long known for their lipid-lowering properties however there has been recent interest in their potential to positively influence clinical outcomes in pulmonary disease processes manifesting primarily as airway disorders. OBJECTIVES: We review the potential use of statin therapy in respiratory medicine, with particular emphasis on airway disease. We also explore the possible mechanisms for the observed benefits of statins in conditions of the airway...
2016: Drug Metabolism Letters
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