384 results match your criteria Drug Metabolism Letters [Journal]


A Practical Perspective on the Evaluation of Small Molecule CNS Penetration in Drug Discovery.

Drug Metab Lett 2019 Mar 11. Epub 2019 Mar 11.

Alliance Pharma, Inc. 17 Lee Blvd. Malvern, PA 19355. United States.

The separation of the brain from blood by the blood-brain barrier and the blood-cerebrospinal fluid (CSF) barrier poses unique challenges for the discovery and development of drugs targeting central nervous system (CNS). This review will describe the role of transporters in CNS penetration and examine the relationship between unbound brain (Cu-brain) and unbound plasma (Cu-plasma) or CSF (CCSF) concentration. Published data demonstrates that the relationship between Cu-brain and Cu-plasma or CCSF can be affected by transporter status and passive permeability of a drug and CCSF may not be a reliable surrogate for CNS penetration. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312813666190311125652DOI Listing
March 2019
2 Reads

Imatinib uptake into cells is not mediated by organic cation transporters OCT1, OCT2, or OCT3, but is influenced by extracellular pH.

Drug Metab Lett 2019 02 7. Epub 2019 Feb 7.

Laboratory of Clinical Pharmacology, Faculty of Biology and Medicine, Lausanne University Hospital, Lausanne . Switzerland.

Background: Cancer cells undergo genetic and environmental changes that can alter cellular disposition of drugs, notably by alterations of transmembrane drug transporters expression. Whether the influx organic cation transporter 1 (OCT1) encoded by the gene SLC221A1 is implicated in the cellular uptake of imatinib is still controversial. Besides, imatinib ionization state may be modulated by the hypoxic acidic surrounding extracellular microenvironment. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312813666190207150207DOI Listing
February 2019
6 Reads

Alam K et al. (2018) Drug Metabolism Letters; 12, 24-32.

Drug Metab Lett 2018 ;12(2):153

Clinical Pharmacology Program, Office of the Clinical Director, and the Molecular Pharmacology Section, Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, MD, United States.

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312812999180724145725DOI Listing
February 2019
18 Reads

A Case Study of Overestimating Absorption and Circulating Metabolites Due to the Preferential Absorption of Radiolabeled Drug in a Mass Balance Study.

Drug Metab Lett 2018 Nov 29. Epub 2018 Nov 29.

Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080. United States.

Background: Mass balance studies conducted using radiolabeled material (14C or 3H) definitively characterize the absorption, metabolism, and excretion (AME) of a drug. A critical aspect of these studies is that the radiotracer maintains its proportion to total drug from its administration to its complete elimination from the body. In the study of GDC-0276 in beagle dogs, we observed that the 14C radiotracer proportion (specific activity) varied through the study. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312813666181129162237DOI Listing
November 2018
13 Reads

"Branched tail" oxyquinoline inhibitors of HIF prolyl hydroxylase: Early Evaluation of Toxicity and Metabolism Using Liver-on-a-chip.

Drug Metab Lett 2018 Nov 28. Epub 2018 Nov 28.

Dmitry Rogachev National Medical Research Center for Pediatric Hematology, Oncology and Immunology, Healthcare Ministry of Russia, 117997 Moscow. Russian Federation.

Background: "Branched tail" oxyquinolines, and adaptaquin in particular, are potent HIF prolyl hydroxylase inhibitors showing promising results in in vivo hemorrhagic stroke models. The further improvement of the potency resulted in identification of a number of adaptaquin analogs. Early evaluation of toxicity and metabolism is desired right at the step of lead selection. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312813666181129100950DOI Listing
November 2018
2 Reads

Transport of Bupropion and its Metabolites by the Model CHO and HEK293 Cell Lines.

Drug Metab Lett 2018 Nov 28. Epub 2018 Nov 28.

Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington 98195. United States.

Background: Bupropion (BUP) is widely used as an antidepressant and smoking cessation aid. There are three major pharmacologically active metabolites of BUP, erythrohydrobupropion (EB), hydroxybupropion (OHB) and threohydrobupropion (TB). At present, the mechanisms underlying the overall disposition and systemic clearance of BUP and its metabolites have not been well understood, and the role of transporters has not been studied. Read More

View Article

Download full-text PDF

Source
http://www.eurekaselect.com/167844/article
Publisher Site
http://dx.doi.org/10.2174/1872312813666181129101507DOI Listing
November 2018
6 Reads

Use of cocktail probe drugs for indexing cytochrome P450 enzymes in clinical pharmacology studies - Review of case studies.

Drug Metab Lett 2018 Nov 19. Epub 2018 Nov 19.

Department of Drug Metabolism and Pharmacokinetics, Zydus Research Centre, Sarkhej-Bavla N.H. No. 8A, Moraiya. Tal: Sanand, Ahmedabad-382 210. India.

Background The cocktail approach of probing drug metabolizing enzymes, in particular cytochrome P450 (CYP) enzymes, is a corner stone in clinical pharmacology studies. The first report of the famous "Pittsburg cocktail" has led the way for the availability of numerous cocktail substrate mixtures that provide options for indexing of CYP enzymes and/or evaluating the perpetrator capacity of the drug. Objectives The key objectives were: 1) to collate, tabulate, and discuss the various cocktail substrates to determine specific CYP enzyme activity in clinical pharmacology studies with specific case studies; 2) to introspect on how the cocktail approach has withstood the test of time and evolved for enabling key decision(s); 3) to provide some futuristic views on the use of cocktail in drug discovery and development. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312812666181119154734DOI Listing
November 2018
15 Reads

Effect of Aqueous Extract of Azadirachta indica Leaves on Pharmacokinetics and Pharmacodynamics of Glipizide.

Drug Metab Lett 2018 Nov 5. Epub 2018 Nov 5.

Phytochemistry Res. Laboratory, Faculty of Pharmacy, Jamia Hamdard, New Delhi-110062. India.

The intake of complementary and alternative medicines leads to various drug interactions, which may affect pharmacodynamics or pharmacokinetics. This study was conducted to determine the interaction of glipizide (GZ) with an aqueous extract of Azadirachta indica (AZI) leaves. The pharmacokinetics and pharmacodynamics were evaluated through the oral glucose tolerance test, high Fat diet (HFD) and streptozotocin-induced diabetes in Wistar rats. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312812666181106115247DOI Listing
November 2018
19 Reads

Comparison of Rat and Human Pulmonary Metabolism Using Precision-Cut Lung Slices (PCLS).

Drug Metab Lett 2018 Oct 22. Epub 2018 Oct 22.

Pharmacokinetic Sciences, Novartis Institutes for Biomedical Research, Basel. Switzerland.

Background: Although the liver is the primary organ of drug metabolism, lungs also contain drug-metabolizing enzymes and may therefore contribute to the elimination of drugs. In this investigation, the precision-cut lung slice (PCLS) technique was standardized with the aims of characterizing and comparing rat and human pulmonary drug metabolizing activity.

Method: Due to the limited availability of human lung tissue, standardization of the PCLS method was performed with rat lung tissue. Read More

View Article

Download full-text PDF

Source
http://www.eurekaselect.com/166496/article
Publisher Site
http://dx.doi.org/10.2174/1872312812666181022114622DOI Listing
October 2018
2 Reads

Hepatic Flavin-containing Monooxygenase and Aldehyde Oxidase Activities in Male Domestic Pigs at Different Ages.

Authors:
Steven X Hu

Drug Metab Lett 2018 ;12(2):125-131

Veterinary Medicine Research and Development, Zoetis, Inc., 333 Portage Street, Kalamazoo, MI 49007, United States.

Background: Age has a significant impact on activities of hepatic metabolizing enzymes in humans and animals. Flavin-containing Monooxygenase (FMO) and Aldehyde Oxidase (AO) are two important hepatic enzymes. Understanding of the impact of age on these two enzymes is still limited in pigs. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312812666180913145334DOI Listing
January 2018
1 Read

Formation of a toxic quinoneimine metabolite from diclofenac: a quantum chemical study.

Drug Metab Lett 2018 Sep 13. Epub 2018 Sep 13.

Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S. A. S. Nagar (Mohali)-160 062. India.

Diclofenac is a non-steroidal antiinflammatory drug. It is predominantly metabolized by CYP2C9. 4̍-hydroxydiclofenac and its quinoneimine are the metabolites of diclofenac. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312812666180913120736DOI Listing
September 2018
1 Read

Preface.

Authors:
Suresh Balani

Drug Metab Lett 2018 ;12(1)

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/187231281201180828160801DOI Listing
January 2019
2 Reads

A Novel In vitro Experimental System for the Evaluation of Enteric Drug Metabolism: Cofactor-Supplemented Permeabilized Cryopreserved Human Enterocytes (MetMax™ Cryopreserved Human Enterocytes).

Drug Metab Lett 2018 ;12(2):132-137

In vitro ADMET Laboratories Inc., 9221 Rumsey Road, Suite 8, Malden, MA 02148, USA and Boston Hepatocyte Technology Center, In vitro ADMET Laboratories, 389 Main St, Ste 301, Malden, MA 02148, United States.

Background: We report here an evaluation of a novel experimental system- cofactorsupplemented permeabilized cryopreserved human enterocytes (MetMax™ cryopreserved human enterocytes (MMHE), patent pending) for applications in the evaluation of enteric drug metabolism. A major advantage of MMHE over Conventional Cryopreserved Human Enterocytes (CCHE) is the simplification of the use procedures including storage at -80°C instead of in liquid nitrogen, and use of the cells immediately after thawing without a need for centrifugation and microscopic evaluation of cell density and viability and cell density adjustment.

Methods: In this study, we compared MMHE and CCHE in key phase 1 oxidation and phase 2 conjugation Drug Metabolism Enzyme (DME) activities that we recently reported for cryopreserved human enterocytes: CYP2C9 (diclofenac 4'- hydroxylation), CYP2C19 (s-mephenytoin hydroxylation), CYP3A4 (midazolam 1'-hydroxylation), CYP2J2 (astemizole O-demethylation), uridine 5'-diphosphoglucuronosyltransferase (UGT; 7-hydroxycoumarin glucuronidation), sulfotransferase (SULT; 7- hydroxycoumarin sulfation), N-acetyl transferase-1 (NAT-1; p-benzoic acid N-acetylation), and carboxyesterase- 2 (CES-2; hydrolysis of irinotecan to SN38). Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312812666180820142141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350199PMC
January 2018
3 Reads

In Vitro Drug-Drug Interaction Potential of Sulfoxide and/or Sulfone Metabolites of Albendazole, Triclabendazole , Aldicarb, Methiocarb, Montelukast and Ziprasidone.

Drug Metab Lett 2018 ;12(2):101-116

Department of Drug Metabolism & Pharmacokinetics, A Division of Cadila Healthcare Ltd., Ahmedabad-382 210, India.

Background: The use of polypharmacy in the present day clinical therapy has made the identification of clinical drug-drug interaction risk an important aspect of drug development process. Although many drugs can be metabolized to sulfoxide and/or sulfone metabolites, seldom is known on the CYP inhibition potential and/or the metabolic fate for such metabolites.

Objective: The key objectives were: a) to evaluate the in vitro CYP inhibition potential of selected parent drugs with sulfoxide/sulfone metabolites; b) to assess the in vitro metabolic fate of the same panel of parent drugs and metabolites. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312812666180816164626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416464PMC
January 2018
6 Reads

Using LC Retention Times in Organic Structure Determination: Drug Metabolite Identification.

Drug Metab Lett 2018 ;12(2):93-100

Department of Drug Metabolism and Pharmacokinetics 1 DNA Way MS 412a, Genentech Inc., South San Francisco, CA 94080, United States.

Background: There is a continued need for improvements in the efficiency of metabolite structure elucidation.

Objective: We propose to take LC Retention Time (RT) into consideration during the process of structure determination.

Methods: Herein, we develop a simple methodology that employs a Chromatographic Hydrophobicity Index (CHI) framework for standardizing LC conditions and introduce and utilize the concept of a predictable CHI change upon Phase 1 biotransformation (CHIbt). Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312812666180802093347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350196PMC
January 2018
7 Reads

Genistein Affects Expression of Cytochrome P450 (CYP450) Genes in Hepatocellular Carcinoma (HEPG2/C3A) Cell Line.

Drug Metab Lett 2018 ;12(2):138-144

Departamento de Biologia Geral, Universidade Estadual de Londrina (UEL), Londrina, Parana, Brazil.

Background: Genistein (5,7-Dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) is the most abundant isoflavone in soybean, which has been associated with a lower risk of development of cancer and cardiovascular diseases. Of particular interest regarding cancer preventive properties of flavonoids is their interaction with cytochrome P450 enzymes (CYPs). However, contradictory data report the effect of genistein on expression of СYPs enzymes. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312812666180709150440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350198PMC
January 2018
7 Reads

Quantitative Proteomics Reveals Changes in Transporter Protein Abundance in Liver, Kidney and Brain of Mice by Pregnancy.

Drug Metab Lett 2018 ;12(2):145-152

Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington DC, 98195, United States.

Background: Few studies have systematically investigated pregnancy-induced changes in protein abundance of drug transporters in organs important for drug/xenobiotic disposition.

Objective: The goal of this study was to compare protein abundance of important drug/xenobiotic transporters including Abcb1a, Abcg2, Abcc2, and Slco1b2 in the liver, kidney and brain of pregnant mice on gestation day 15 to that of non-pregnant mice.

Methods: The mass spectrometry-based proteomics was used to quantify changes in protein abundance of transporters in tissues from pregnant and non-pregnant mice. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312812666180625122810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350206PMC
January 2018
19 Reads

New Perspectives on Acyl Glucuronide Risk Assessment in Drug Discovery: Investigation of In vitro Stability, In situ Reactivity, and Bioactivation.

Drug Metab Lett 2018 ;12(2):84-92

Novartis Institutes for BioMedical Research, Inc., Pharmacokinetic Sciences, Global Biotransformation, Cambridge, Watertown, MA 02139, United States.

Background: Acyl glucuronides of xenobiotics have been a subject of wide interest from the pharmaceutical industry with respect to biochemical reactivity, hepatic disposition, and enterohepatic circulation. The reactivity and lack of stability of an acyl glucuronide for a clinical candidate could pose major developability concerns. To date, multiple in vitro assays have been published to assess the risk associated with acyl glucuronides. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312812666180611113656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350207PMC
January 2018
6 Reads

Effects of Tobacco Nicotine-Derived Nitrosamine Ketone (NNK) Exposures on Brain Alcohol Metabolizing Enzyme Activities.

Drug Metab Lett 2018 ;12(2):117-124

Liver Research Center, Division of Gastroenterology and Department of Medicine, Rhode Island Hospital and The Alpert Medical School of Brown University, Providence, RI, United States.

Background: The high levels of blood alcohol achieved with chronic plus binge alcohol exposures are somewhat reduced by co-administration of tobacco-specific Nicotine-Derived Nitrosamine Ketone (NNK) suggesting that NNK may alter alcohol metabolism.

Objective: We examined ethanol and acetaldehyde-metabolizing enzyme activities and malondialdehyde adduct formation in rats exposed to ethanol (chronic + binge), NNK, or both.

Methods: 4-week old Long Evans rats were fed liquid diets containing 0% or 26% caloric ethanol for 8 weeks. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312812666180611115418DOI Listing
January 2018
6 Reads

Effect of CYP2D6 Poor Metabolizer Phenotype on Stereoselective Nebivolol Pharmacokinetics.

Drug Metab Lett 2018 ;12(1):68-70

Departamento de Analises Clinicas, Toxicologicas e Bromatologicas, Faculdade de Ciencias Farmaceuticas de Ribeirao Preto, Universidade de Sao Paulo, Ribeirao Preto, Brazil.

Background: Nebivolol is a drug available as a racemate of d-nebivolol (SRRR) and lnebivolol (RSSS). In human liver microsomes, CYP2D6 mainly catalyses the metabolism of lnebivolol, while CYP2C19 catalyses the metabolism of d-nebivolol. Nebivolol stereoselective pharmacokinetics has been described only for extensive metabolizers (EM). Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312812666180420104945DOI Listing
January 2019
6 Reads

In vitro Drug Metabolism Investigation of 7-Ethoxycoumarin in Human, Monkey, Dog and Rat Hepatocytes by High Resolution LC-MS/MS.

Drug Metab Lett 2018 ;12(1):33-53

Drug Metabolism and Pharmacokinetics, Dart NeuroScience, San Diego, CA 92131, United States.

Background: Recently, it has been an increasing concern on the bioactivation and adverse reactions associated with consumption of herbal and nature products. 7-Ethoxycoumarin is one of coumarin family compounds, but little information is available regarding its potential reactive metabolites.

Method: 7-ethoxylcoumarin was incubated individually with human, monkey, dog and rat hepatocytes for 2 hr, metabolites were detected, identified and characterized using high resolution liquid chromagraphy - tandem mass spectrometry. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312812666180418142056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416465PMC
January 2019
3 Reads

Evaluation of the Effect of Uremic Serum on Hepatic Reductase Functional Expression.

Drug Metab Lett 2018 ;12(1):75-81

Department of Internal Medicine, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan.

Background: The nonrenal clearance of drugs mediated by hepatic reduction is selectively altered by kidney disease. This study evaluated the influence of uremic serum on the expression and activity of reductase enzymes.

Methods: Human hepatocellular carcinoma cells (HepG2) were incubated with 5% pooled serum collected from patients with hemodialysis (pre- and post-dialysis session) or control subjects. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312812666180416154436DOI Listing
January 2019
5 Reads

Cytochrome P450 3A4 Induction: Lumacaftor versus Ivacaftor Potentially Resulting in Significantly Reduced Plasma Concentration of Ivacaftor.

Drug Metab Lett 2018 ;12(1):71-74

Department of Pharmacology & Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC 3010, Australia.

Background & Objective: Since the release of ivacaftor-lumacaftor, several red-flags have been raised that highlight the clinical efficacy of this combination strategy that may be limited due to antagonistic drug-drug interactions.

Method: The effect of ivacaftor, its major metabolites M1 and M6, lumacaftor and the novel cystic fibrosis transmembrane conductance regulator (CFTR) modulator tezacaftor at 10 µg/mL on the enzymatic activity of the major xenobiotic metabolizing enzymes CYP1A2 and CYP3A4 as well as the minor enzymes CYP2B6 and CYP2C9 was assayed.

Results: Lumacaftor (3. Read More

View Article

Download full-text PDF

Source
http://www.eurekaselect.com/160801/article
Publisher Site
http://dx.doi.org/10.2174/1872312812666180328105259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350194PMC
January 2019
16 Reads

Characterization of Liver- and Cancer-type-Organic Anion Transporting Polypeptide (OATP) 1B3 Messenger RNA Expression in Normal and Cancerous Human Tissues.

Drug Metab Lett 2018 ;12(1):24-32

Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States.

Background: Membrane transport protein organic anion transporting polypeptide (OATP) 1B3 mediates the cellular uptake of many clinically important drugs including anti-cancer drugs (e.g., paclitaxel). Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312812666180326110146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133766PMC
January 2019
5 Reads

Evaluation of Herb-Drug Interaction of Synacinn™ and Individual Biomarker through Cytochrome 450 Inhibition Assay.

Drug Metab Lett 2018 ;12(1):62-67

Drug Metabolism and Pharmacokinetics, Aurigene Discovery Technologies, Ltd. Bollaram Road, Miyapur Hyderabad 500 049, Telangana, India.

Background: SynacinnTM contains five standardized herbal extracts of Orthosiphon Stamineus (OS), Syzygium polyanthum (SZ), Curcuma xantorrizza (CX), Cinnamomum zeylanicum (CZ) and Andrographis paniculata (AP) and is standardized against phytochemical markers of rosmarinic acid, gallic acid, curcumin, catechin and andrographolide respectively. This herbal medicine has been used as health supplement for diabetes. SynacinnTM is recommended to be consumed as supplement to the diabetic drugs. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312812666180314112457DOI Listing
January 2019
9 Reads

LC-MS/MS Identification and Structural Characterization of Main Biodegradation Products of Nitroproston - A Novel Prostaglandin-based Pharmaceutical Compound.

Drug Metab Lett 2018 ;12(1):54-61

Institute of Pharmacy and Translational Medicine, Sechenov First Moscow State Medical University (Sechenov University), Moscow, 119991, Russian Federation.

Background: Nitroproston is a novel prostaglandin-based compound modified by NOdonating groups with potential application in obstructive respiratory diseases such as asthma and obstructive bronchitis. Nitroproston has been extensively studied using various pharmacological models. Its biological stability is still uncertain. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312812666180309160927DOI Listing
January 2019
25 Reads

Cytochrome P450 1A2 Messenger RNA is a More Reliable Marker than Cytochrome P450 1A2 Activity, Phenacetin O-Deethylation, for Assessment of Induction Potential of Drug-Metabolizing Enzymes Using HepaRG Cells.

Drug Metab Lett 2018;12(1):14-23

Department of Regeneration Medicine, Yokohama City University School of Medicine, Yokohama, Japan.

Background: The HepaRG cells have key drug metabolism functionalities comparable to those of primary human hepatocytes. Many studies have reported that this cell line can be used as a reliable in vitro model for human drug metabolism studies, including the assessment of cytochrome P450 (CYP) induction.

Objectives: The objective of this study is to determine whether CYP mRNA level measurement is superior to the CYP enzyme activity measurement as a convenient high-throughput method for evaluating CYP induction potential using HepaRG cells. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312812666180119114013DOI Listing
January 2019
10 Reads

Evaluation of Farnesoid X Receptor Target Gene Induction in Human Hepatocytes: Amino Acid Conjugation.

Drug Metab Lett 2017;11(2):138-143

Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492, United States.

Background: The nuclear hormone receptor, Farnesoid X Receptor (FXR) regulates the transcription of genes associated with bile acid metabolism and disposition.

Objective: This study investigates possible changes in the expression of target genes responsible for amino acid conjugation, i.e. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312812666171227213946DOI Listing
October 2018
6 Reads

Utility of Pooled Cryopreserved Human Enterocytes as an In vitro Model for Assessing Intestinal Clearance and Drug-Drug Interactions.

Drug Metab Lett 2018;12(1):3-13

Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., South San Francisco, CA, 94080, United States.

Background: A recent advancement in isolation and cryopreservation has resulted in commercially available primary human enterocytes that express various drug metabolizing enzymes (DMEs) and transporters. The main objective of this study was to further evaluate the utility of pooled cryopreserved enterocytes, specifically MetMax™ cryopreserved human enterocytes (In vitro ADMET Laboratories), as an in vitro model for assessing intestinal clearance in comparison to hepatocytes.

Methods: It was found that, for CYP3A4/5 substrates such as midazolam, amprenavir and loperamide, in vitro metabolic clearance is generally lower in enterocytes compared to that of hepatocytes, which is consistent with the relative abundance of the enzyme between the intestine and liver. Read More

View Article

Download full-text PDF

Source
http://www.eurekaselect.com/158255/article
Publisher Site
http://dx.doi.org/10.2174/1872312812666171213114422DOI Listing
January 2019
33 Reads

Transactivation Assays that Identify Indirect and Direct Activators of Human Pregnane X Receptor (PXR, NR1I2) and Constitutive Androstane Receptor (CAR, NR1I3).

Drug Metab Lett 2017;11(2):128-137

Puracyp, Inc., Carlsbad, CA 92010, United States.

Background: Nuclear Receptors (NRs), including PXR and CAR, are presumed to be ligand-dependent transcription factors, but ligand binding is not an absolute requirement for activation. Indeed, many compounds activate PXR and CAR by indirect mechanisms. Detecting these indirect activators of specific nuclear receptors in vitro has been difficult. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312812666171207113639DOI Listing
October 2018
7 Reads

Preface.

Authors:
Suresh K Balani

Drug Metab Lett 2017 Nov;11(1)

Takeda Pharmaceuticals,International Company Cambridge, MA . United States.

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/187231281101171117161507DOI Listing
November 2017
3 Reads

Selective Suppression of CYP3A4 mRNA and Enzyme Activity by Epidermal Growth Factor in Plated Human Hepatocytes.

Drug Metab Lett 2017;11(2):119-127

Corning Gentest Contract Research Services, Corning Life Sciences, Woburn, MA 01801, United States.

Background: Epidermal Growth Factor (EGF) is a well-known mitogen that has importance in cell proliferation and differentiation. This property has led to the common use of EGF as an additive to some cell culture media. EGF has been previously shown to modulate constitutive Cytochrome P450 (CYP) expression in vitro. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312811666171128141105DOI Listing
October 2018
10 Reads

Therapeutic Potentials and Cytochrome P450-Mediated Interactions Involving Herbal Products Indicated for Diabetes Mellitus.

Drug Metab Lett 2017 ;11(2):74-85

Department of Clinical Pharmacy and Pharmacy Administration, Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife, Nigeria.

Background: There has been an increase in the use of herbal products to complement conventional drugs in the treatment of various diseases especially in developing countries. This may be attributable to the potential cost-effectiveness and ease of accessibility of these products as well as the perception of their safety profiles. However, there are numerous literature reports on herbs altering the pharmacokinetics and pharmacodynamics of other co-administered drugs thereby modulating the therapeutic outcomes. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312811666171121104431DOI Listing
October 2018
14 Reads

Analysis of Elevated Levels of Nandrolone Decanoate Induced Cytochrome- P450 Alterations in Mice.

Drug Metab Lett 2017 ;11(2):86-92

Department of Zoology, Faculty of Sciences, Cotton College, Guwahati, Assam, India.

Background: Frequent recreational use of Anabolic Androgenic Steroids (AAS) is an instance of substance abuse which mimics the status of a natural hormone and upon prolonged exposure may lead to adverse drug reactions. These adverse drug reactions proceed in a manner so as to alter the normal metabolism of an enzyme mediated pathway such as the Cytochrome P450 (CYP) family of enzymes.

Objective: The present study was conducted to investigate the impact of overuse of Nandrolone Decanoate (ND), an AAS, upon CYP enzyme activity and a CYP gene, belonging to CYP1 family. Read More

View Article

Download full-text PDF

Source
http://www.eurekaselect.com/157154/article
Publisher Site
http://dx.doi.org/10.2174/1872312811666171114145535DOI Listing
October 2018
17 Reads

Genotoxicity of 4-(piperazin-1-yl)-8-(trifluoromethyl)pyrido[2,3-e][1,2,4] triazolo[4,3-a]pyrazine, a Potent H4 Receptor Antagonist for the Treatment of Allergy: Evidence of Glyoxal Intermediate Involvement.

Drug Metab Lett 2017;11(2):144-148

PK Sciences, Global Biotransformation, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, United States.

Background: 4-(piperazin-1-yl)-8-(trifluoromethyl)pyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (1) is a small-molecule which demonstrated a sub-nM inhibitory potency toward the histamine H4 receptor (H4R). However, it was found to be mutagenic in an in vitro Ames assay. Metabolic bioactivation of 1 could potentially arise from the piperazine moiety by forming reactive intermediates such as glyoxal, aldehyde-imine and/or iminium ion, which could all lead to genotoxicity. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312811666171106151730DOI Listing
October 2018
11 Reads

The Effects of Drug Metabolizing Enzyme Inhibitors on Hepatic Efflux and Uptake Transporters.

Drug Metab Lett 2017;11(2):111-118

Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc. South San Francisco, CA, United States.

Background: Non-selective chemical inhibitors of phase I and phase II enzymes are commonly used in in vitro metabolic studies to elucidate the biotransformation pathways of drugs. However, the inhibition of the inhibitors on efflux and uptake transporters is not well investigated, potentially leading to unexpected and ambiguous results in these studies.

Objective: The commonly used metabolizing enzyme inhibitors, 1-aminobenzotriazole (ABT), SKF- 525A, pargyline, allopurinol, menadione, methimazole, piperine and raloxifene, were examined for their potential inhibition of the major hepatic ABC (ATP binding cassette) and SLC (solute carrier) transporters. Read More

View Article

Download full-text PDF

Source
http://www.eurekaselect.com/156306/article
Publisher Site
http://dx.doi.org/10.2174/1872312811666171010101248DOI Listing
October 2018
14 Reads

Investigation of Ocular Bioactivation Potential and the Role of Cytochrome P450 2D Enzymes in Rat.

Drug Metab Lett 2017;11(2):102-110

Analytical Sciences and Imaging, Novartis Institutes for BioMedical Research, Inc., Cambridge, MA, USA.

Background: Timolol is clinically administered topically (ocular) to reduce intraocular pressure and treat open-angle glaucoma. Ocular administration of timolol in low doses (0.5% w/v in the form of eye drops) has led to challenges for in vivo metabolite identification. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312811666170911122919DOI Listing
October 2018
44 Reads

A Pharmacokinetic-Pharmacodynamic Model of Tamoxifen and Endoxifen to Predict Their Distribution and Effects on Inhibition of Tumor Growth.

Drug Metab Lett 2017 ;11(2):93-101

School of Science, China Pharmaceutical University, Nanjing, China.

Background: Tamoxifen is widely used in the therapy for breast cancer and has three major metabolites, N-desmethyltamoxifen, 4-hydroxytamoxifen, and endoxifen. Endoxifen has played a major role in the inhibition of tumor growth of breast cancer and the tumor growth is related to endoxifen concentration.

Objectives: The aim of this study was to develop a pharmacokinetic-pharmacodynamic model to predict the distribution of tamoxifen and endoxifen quantitatively, and to discover the anti-tumor effect patterns of tamoxifen and endoxifen. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312811666170815160751DOI Listing
October 2018
13 Reads

Quantification of Sulfotransferases 1A1 and 1A3/4 in Tissue Fractions and Cell Lines by Multiple Reaction Monitoring Mass Spectrometry.

Drug Metab Lett 2017 11;11(1):35-47

Otsuka Maryland Medicinal Laboratories, Rockville, MD 20850, USA.

Background: Within the sulfotransferase (SULT) superfamily of metabolic enzymes, SULT1A1 and 1A3/4 isoforms are of particular interest, due to their abilities to catalyze the sulfation of phenolic endobiotics and xenobiotics. Although the difference in their substrate specificity is well documented, an isoform-specific quantification method is still not available.

Objective: To detect and quantify SULT1A1 and 1A3/4 in S9 fractions and cell lines using targeted mass spectrometry-based proteomics. Read More

View Article

Download full-text PDF

Source
http://www.eurekaselect.com/154600/article
Publisher Site
http://dx.doi.org/10.2174/1872312811666170731170153DOI Listing
November 2017
13 Reads

Mixed Matrix Method Provides A Reliable Metabolite Exposure Comparison for Assessment of Metabolites in Safety Testing (MIST).

Drug Metab Lett 2017 11;11(1):21-28

Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

Background: The regulatory guidances on metabolites in safety testing (MIST) by US Food and Drug Administration (FDA) and International Conference on Harmonisation (ICH) describe the necessity to assess exposures of major circulating metabolites in humans at steady state relative to exposures achieved in nonclinical safety studies prior to the initiation of large scale clinical trials. This comparison can be accomplished by measuring metabolite concentrations in animals and humans with validated bioanalytical methods. However, bioanalysis of metabolites in multiple species and multiple studies is resource intensive and may impact the timelines of clinical studies. Read More

View Article

Download full-text PDF

Source
http://www.eurekaselect.com/154106/article
Publisher Site
http://dx.doi.org/10.2174/1872312811666170710193229DOI Listing
November 2017
16 Reads

Potential Minor Haplotypes of CYP2D6 in the Japanese Population.

Drug Metab Lett 2017 11;11(1):53-59

Headquarters of Clinical Development, Otsuka Pharmaceutical Co., Ltd., Osaka, Japan.

Background: CYP2D6 is one of the most significant polymorphic genes of drugmetabolizing enzymes due to its association with different metabolic activities and the pharmacokinetics of CYP2D6 substrates.

Objective: The objective of this study was to explore for a novel haplotype of CYP2D6 in the Japanese population by using a large database of previous clinical studies.

Methods: We analyzed CYP2D6 genotype data from a total of 723 Japanese individuals for 8 loci (100C>T, 1758G>A, 1846G>A, 2573 insertion of C, 2850C>T, 2988G>A, 4125 insertion of 9bp, and 4180G>C) and gene deletion. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312811666170613080221DOI Listing
November 2017
48 Reads

The Role of Placental Carbonyl Reducing Enzymes in Biotransformation of Bupropion and 4-methylnitrosamino-1-(3-pyridyl)-1-butanone.

Drug Metab Lett 2017 11;11(1):29-34

Maternal-Fetal Pharmacology and Biodevelopment Laboratories, Department of Obstetrics & Gynecology, The University of Texas Medical Branch at Galveston, TX, USA.

Background: Bupropion (BUP) has a potential to be an effective pharmacotherapy for smoking cessation during pregnancy. Smoking during pregnancy stimulates placental carbonyl reductases that catalyze the biotransformation of BUP. 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) is a potent carcinogen of cigarette smoke. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312811666170607095202DOI Listing
November 2017
20 Reads

Metabolic Profile of Flunitrazepam: Clinical and Forensic Toxicological Aspects.

Drug Metab Lett 2017 11;11(1):14-20

IINFACTS - Institute of Research and Advanced Training in Health Sciences and Technologies, Department of Sciences, University Institute of Health Sciences (IUCS), CESPU, CRL, Gandra, Portugal.

Background: Flunitrazepam (FNZ) is a potent hypnotic, sedative, and amnestic drug used to treat insomnia and as a pre-anesthetic agent. The illicit practice in drug-facilitated sexual assault led to important clinical and forensic concerns.

Objective: In this work the metabolism of FNZ, and pharmacological- and toxicological-related effects, were fully reviewed. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312811666170407164216DOI Listing
November 2017
9 Reads

Effects of Fenofibrate on the Expression of Small Heterodimer Partner (SHP) and Cytochrome P450 (CYP) 2D6.

Drug Metab Lett 2017 11;11(1):68-72

Department of Pharmacy Practice (H.J.); Department of Biopharmaceutical Sciences (R.K., H.J.), College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA.

Background: Cytochrome P450 (CYP) 2D6 is a major drug-metabolizing enzyme, responsible for eliminating 25% of marketed drugs. We recently identified SHP as a negative regulator of CYP2D6 expression and showed that factors that alter SHP expression influence CYP2D6 expression. Fenofibrate, an agonist of peroxisome proliferator-activated receptor α(PPARα), has been previously reported to upregulate SHP expression in the mouse liver. Read More

View Article

Download full-text PDF

Source
http://www.eurekaselect.com/151454/article
Publisher Site
http://dx.doi.org/10.2174/1872312811666170407164631DOI Listing
November 2017
9 Reads

Gender Difference of Hepatic and Intestinal CYP3A4 in CYP3AHumanized Mice Generated by a Human Chromosome-engineering Technique.

Drug Metab Lett 2017 11;11(1):60-67

Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan.

Background: Cytochrome P450 3A4 (CYP3A4) is an important drug-metabolizing enzyme that is expressed in the liver and small intestine of humans. Various factors influence the expression of CYP3A4, but gender difference in CYP3A4 expression remains debatable.

Objective: To clarify gender difference of hepatic and intestinal CYP3A4 in CYP3A-humanized mice generated by a human artificial chromosome (HAC) vector system. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312811666170404153804DOI Listing
November 2017
9 Reads

Inhibitory Effect of Fruit Juices on the Doxorubicin Metabolizing Activity of Carbonyl Reductase 1.

Drug Metab Lett 2017 11;11(1):48-52

Laboratory of Biochemistry, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-kita, Tondabayashi, Osaka 584-8540, Japan.

Background And Objective: Doxorubicin, an anthracycline anti-cancer drug, is effective for breast cancer and childhood lymphoma. Chronic cardiotoxicity has been known as a critical adverse effect of doxorubicin and is attributed to its metabolite doxorubicinol produced by carbonyl reductase 1 (CBR1, SDR21C1). Some flavonoids have been reported to act as inhibitors for CBR1, therefore, commercially available juices containing flavonoids are likely to be applicable as a prophylactic treatment against doxorubicin-induced cardiotoxicity by suppression of doxorubicinol production. Read More

View Article

Download full-text PDF

Source
http://www.eurekaselect.com/150794/article
Publisher Site
http://dx.doi.org/10.2174/1872312811666170309153025DOI Listing
November 2017
11 Reads

Obesity and Inflammation and Altered Clopidogrel Pharmacokinetics and Pharmacodynamics.

Drug Metab Lett 2017 11;11(1):3-13

Department of Pharmacy Practice, Clinical Assistant Professor, University at Buffalo School of Pharmacy & Pharmaceutical Sciences, Buffalo, NY. United States.

Background: Clopidogrel is a key antiplatelet drug that has substantial interpatient variability in pharmacodynamic response. Patients with lesser degrees of platelet inhibition in response to clopidogrel appear to be at increased risk of cardiovascular events. Obesity is an independent risk factor for cardiovascular morbidity and mortality due to atherothrombotic events and represents a group of patients who are in need of optimized antithrombotic therapy. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312811666170301110349DOI Listing
November 2017
9 Reads

The Metabolism of Methazolamide in Immortalized Human Keratinocytes, HaCaT Cells.

Drug Metab Lett 2017 ;10(4):295-305

Department of Biochemistry, Akita University Graduate School of Medicine, Hondo, Akita 010-8543. Japan.

Objective: Drug therapy is occasionally accompanied by an idiosyncratic severe toxicity, which occurs very rarely, but can lead to patient mortality. Methazolamide, an anti-glaucomatous agent, could cause severe skin eruptions called Stevens-Johnson syndrome/toxic epidermal necrolyis (SJS/TEN). Its precise etiology is still uncertain. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312811666170127160931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5403967PMC
May 2018
42 Reads

Pharmacokinetics, Metabolism and Disposition of [14C]XQ-1H After Intravenous Administration to Male Rats.

Drug Metab Lett 2017 ;10(4):228-239

XBLChina, Inc., a Subsidiary of LTD, WuXi AppTec, Nanjing, Jiangsu 210038. China.

Objective: This study describes the in vivo pharmacokinetics and metabolism of [14C]labeled XQ-1H in male rats.

Methods: XQ-1H is a methanesulfonate of XQ, 10-O-(N,N-dimethylaminoethyl)-ginkgolide B, a derivative of ginkgolide B (GB) with enhanced water solubility. Since it is very difficult to synthesize radiolabeled GB, the results obtained in this study may provide helpful insight to further ADME investigation of GB and its analogue compounds. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312811666170118162931DOI Listing
May 2018
19 Reads

Quantification of Etodolac in Human Plasma for Pharmacokinetics and Bioequivalence Studies in 27 Korean Subjects.

Drug Metab Lett 2017 ;10(4):286-294

Department of Biomedical Engineering, College of Engineering, University of Wisconsin-Madison, Wisconsin. United States.

Objective: We developed a simple and validated liquid chromatography tandem mass spectrometry( LC-MS/MS) for quantification of etodolac using pioglitazone as an internal standard (IS) to assess pharmacokinetics and to appraise bioequivalence of two formulations of etodolac (reference and tested) in 27 healthy Korean subjects.

Methods: Isocratic mobile phase consisted of 10 mM ammonium formate and acetonitrile were used to separate the analytes on a Gemini C18 column. Also, analytes were analyzed by MS/MS in multiple reaction monitoring (MRM) mode using the transitions of (M+H)+ ions, m/z 288. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2174/1872312811666170116151004DOI Listing
May 2018
28 Reads