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Expert Opinion on Drug Metabolism & Toxicology

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https://www.readbyqxmd.com/read/29897844/pharmacokinetic-drug-evaluation-of-rifaximin-for-treatment-of-diarrhea-predominant-irritable-bowel-syndrome
#1
Eugenia Bruzzese, Marcella Pesce, Giovanni Sarnelli, Alfredo Guarino
INTRODUCTION: Rifaximin is a poorly absorbable antibiotic with a broad-spectrum activity against both Gram-negative and -positive bacteria. It is active in the small intestine due to its high bile solubility, whereas in the aqueous environment of the colon, it shows limited efficacy against highly susceptible bacteria. These unique pharmacokinetic properties limit its systemic effects and can correct gut microflora imbalances. Thus, rifaximin has become a major therapeutic agent in several gastrointestinal diseases in which an imbalance in gut microflora may play a role, including diarrhea predominant irritable bowel syndrome (IBS-D)...
June 13, 2018: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/29897249/a-randomized-study-investigating-the-effect-of-omeprazole-on-the-pharmacokinetics-of-oral-semaglutide
#2
Tine A Bækdal, Astrid Breitschaft, Andrea Navarria, Cilie W Hansen
Background Since the first oral glucagon-like peptide-1 analog comprises semaglutide co-formulated with an absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC), which induces a transient, localized increase in gastric pH, we have investigated whether a proton pump inhibitor affects the pharmacokinetics of oral semaglutide. Research design and methods A single-center, randomized, open-label, parallel-group trial investigated pharmacokinetic interactions of oral semaglutide with omeprazole (40 mg once-daily) in fifty-four healthy subjects...
June 13, 2018: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/29888962/predicting-drug-induced-cholestasis-preclinical-models
#3
Petar D Petrov, M Leonor Fernández-Murga, Mireia López-Riera, M José Goméz-Lechón, Jose V Castell, Ramiro Jover
In almost 50% of patients with drug-induced liver injury (DILI) the bile flow from the liver to the duodenum is impaired, a condition known as cholestasis. However, this toxic response only appears in a small percentage of the treated patients (idiosyncrasy). Prediction of drug-induced cholestasis is challenging and emerges as a safety issue that requires attention by professionals in clinical practice, regulatory authorities, pharmaceutical companies and research institutions. Area covered: The current synopsis focuses on the state-of-the-art in preclinical models for cholestatic DILI prediction...
June 11, 2018: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/29888644/regulation-of-cytochrome-p450-gene-expression-by-ketamine-a-review
#4
Jui-Tai Chen, Li Wei, Ta-Liang Chen, Chun-Jen Huang, Ruei-Ming Chen
Although used as an anesthetic drug for decades, ketamine appears to have garnered renewed interest due to its potential therapeutic uses in pain therapy, neurology, and psychiatry. Ketamine undergoes extensive oxidative metabolism by cytochrome P450 (CYP) enzymes. Considerable efforts have been expended to elucidate the ketamine-induced regulation of CYP gene expression. The safety profile of chronic ketamine administration is still unclear. Understanding how ketamine regulates CYP gene expression is clinically meaningful...
June 10, 2018: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/29886753/interactions-of-pesticides-with-membrane-drug-transporters-implications-for-toxicokinetics-and-toxicity
#5
Lisa Chedik, Arnaud Bruyere, Astrid Bacle, Sophie Potin, Marc Le Vée, Olivier Fardel
Drug transporters are now recognized as major actors of pharmacokinetics. They are also likely implicated in toxicokinetics and toxicology of environmental pollutants, notably pesticides, to which humans are widely exposed and which are known to exert various deleterious effects towards health. Interactions of pesticides with drug transporters are therefore important to consider. Areas covered: This review provides an overview of the interactions of pesticides with membrane drug transporters, i.e., inhibition of their activity, regulation of their expression and handling of pesticides...
June 10, 2018: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/29865879/the-potential-effects-of-ocimum-basilicum-on-health-a-review-of-pharmacological-and-toxicological-studies
#6
P Sestili, T Ismail, C Calcabrini, M Guescini, E Catanzaro, E Turrini, A Layla, S Akhtar, C Fimognari
Basil (Ocimum basilicum L., OB) is a plant world widely used as a spice and a typical ingredient of the healthy Mediterranean diet. In traditional medicine, OB is indicated for many maladies and conditions; OB-containing nutritional supplements are increasingly sold. Conversely, safety concerns have been raised about the promutagens and procarcinogens alkenylbenzenes contained in OB. Areas covered: A critical review of the current status of OB as a nutraceutical, the pharmacology of its bioactive components, the rationale for its indications, and its safety...
June 4, 2018: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/29865877/new-paradigm-for-rapid-achievement-of-appropriate-therapy-in-special-populations-coupling-antibiotic-dose-optimisation-rapid-microbiological-methods
#7
Mohd H Abdul-Aziz, Elicia Driver, Jeffrey Lipman, Jason A Roberts
Some special patient populations (e.g. critically ill, burns, haematological malignancy, post-major surgery, post-major trauma) have characteristics that lead to higher rates of failure and mortality associated with infection. Choice of effective antibiotics and optimised doses are challenging in these patients that are commonly infected by multi-drug resistant pathogens Areas covered: A review of the importance of diagnosis and the place of newer microbiological methods (e.g. whole genome sequencing) to ensure rapid transition from empiric to directed antibiotic therapy is provided...
June 4, 2018: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/29865869/the-optimal-dose-of-disease-specific-antibodies-for-post-exposure-prophylaxis-of-measles-and-rubella-in-australia-new-guidelines-recommended
#8
Megan K Young, Shu-Kay Ng, Graeme R Nimmo, Allan W Cripps
BACKGROUND: It is unclear whether recommended doses of intramuscular polyvalent immune globulin are optimal for both effectiveness and efficiency of disease prevention when administered post-exposure to measles and rubella. METHODS: The peak concentration and decay of disease-specific antibodies after intramuscular dosing of polyvalent immune globulin in adults was modelled using published pharmacokinetic parameters and product disease-specific antibody concentrations...
June 4, 2018: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/29863909/opportunities-and-obstacles-in-genotypic-prediction-of-cytochrome-p450-phenotypes
#9
Joseph McGraw, Armin Gerhardt, Tommy C Morris
No abstract text is available yet for this article.
June 4, 2018: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/29855221/pharmacokinetic-and-pharmacodynamic-evaluation-of-daclatasvir-asunaprevir-plus-beclabuvir-as-a-fixed-dose-co-formulation-for-the-treatment-of-hepatitis-c
#10
Isabella Esposito, Sebastián Marciano, Julieta Trinks
Many reports have evaluated the clinical efficacy and safety of the fixed-dose all-oral combination of daclatasvir, asunaprevir and beclabuvir (DCV-TRIO), which was approved in Japan in December 2016 for the treatment of hepatitis C genotype 1 infection. Areas covered: This article reviews the pharmacodynamic and pharmacokinetic properties of the DCV-TRIO combination. The topics covered include data regarding the drug's absorption, distribution, metabolism, excretion and antiviral activity strategies. Its therapeutic efficacy and safety in genotype 1 infection from phase 2/3 clinical trials are also discussed...
June 1, 2018: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/29848078/influence-of-ethanol-on-the-metabolism-of-alprazolam
#11
Zhibin Huang, Zhiru Xu, Hao Wang, Ziqin Zhao, Yulan Rao
BACKGROUND: Alprazolam is one of the most commonly used benzodiazepines in clinical practice, and when coingested with ethanol, alprazolam can increase behavioral irritability and aggression. However, the mechanism of its interaction with ethanol remains unknown. RESEARCH DESIGN AND METHODS: The pharmacokinetics of alprazolam were studied in vivo in rat experiments involving the simultaneous administration of alprazolam and ethanol, and the interactions between ethanol and alprazolam were investigated in vitro in human liver microsomes...
May 31, 2018: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/29847748/peroxisome-proliferator-activated-receptor-alpha-mediated-drug-toxicity-in-the-liver
#12
Maka S Hedrington, Stephen N Davis
Drug-induced hepatic injury is the most common cause of acute liver failure in the United States. Included among the approximately 900 natural and synthetic substances that have shown hepatotoxicity are peroxisome proliferator-activated receptor alpha (PPARα)-mediated drugs. Areas covered: This review will focus on fibrates - PPARα agonists and their implication in causing liver injury. Expert opinion: Compelling evidence for fibrate-induced hepatotoxicity is not available. Results have been variable with several large randomized clinical trials reporting similar elevations of plasma transaminase levels in fibrate or placebo treated groups...
May 30, 2018: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/29842801/an-update-on-efflux-and-uptake-transporters-as-determinants-of-statin-response
#13
Karina Cunha E Rocha, Beatriz Maria Veloso Pereira, Alice Cristina Rodrigues
Statins are used in the treatment of dyslipidemia promoting primary and secondary prevention against detrimental cardiovascular events. ATP-binding cassette (ABC) and solute carrier (SLC) membrane transporters transport statins across the cell membrane. Differences in drug transporter tissue expression and activity contribute to variability in statin pharmacokinetics (PK) and response. Areas covered: The purpose of this review is to discuss factors impacting transporter expression and the effect this has on statin efficacy and safety...
May 29, 2018: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/29806951/an-update-on-the-potential-role-of-intestinal-first-pass-metabolism-for-the-prediction-of-drug-drug-interactions-the-role-of-pbpk-modeling
#14
Saeed Alqahtani, Ishfaq Bukhari, Ahmed Albassam, Maha Alenazi
The intestinal absorption process is a combination of several events that are governed by various factors. Several transport mechanisms are involved in drug absorption through enterocytes via active and/or passive processes. The transported molecules then undergo intestinal metabolism, which together with intestinal transport may affect the systemic availability of drugs. Many studies have provided clear evidence on the significant role of intestinal first-pass metabolism on drug bioavailability and degree of drug-drug interactions (DDIs)...
May 28, 2018: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/29788828/mechanistic-kinetic-modeling-generates-system-independent-p-glycoprotein-mediated-transport-elementary-rate-constants-for-inhibition-and-in-combination-with-3d-sim-microscopy-elucidates-the-importance-of-microvilli-morphology-on-p-glycoprotein-mediated-efflux
#15
Harma Ellens, Zhou Meng, Sylvain J Le Marchand, Joe Bentz
Introduction In vitro transporter kinetics are typically analyzed by steady-state Michaelis-Menten (MM) approximations. However, no clear evidence exists that these approximations, applied to multiple transporters in biological membranes, yield system-independent mechanistic parameters needed for reliable in vivo hypothesis generation and testing. Areas covered The classical mass action model has been developed for P-glycoprotein mediated transport across confluent polarized cell monolayers. Numerical integration of the mass action equations for transport using a stable global optimization program, yields fitted elementary rate constants that are system-independent...
May 23, 2018: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/29775551/pharmacogenetic-associations-with-cytochrome-p450-in-antiretroviral-therapy-what-does-the-future-hold
#16
Gabriel Stillemans, Leila Belkhir, Dennis A Hesselink, Vincent Haufroid, Laure Elens
Several antiretroviral drugs used to treat infection with the Human Immunodeficiency Virus (HIV) are substrates of enzymes belonging to the cytochrome P450 (CYP) superfamily, which are polymorphically expressed. It may therefore be useful to take into account the genetic variation in these enzymes to predict the likelihood of anti-HIV treatment success, toxicity and the potential for drug-drug interactions. Areas covered: In this manuscript, the authors discuss the current state of knowledge regarding pharmacogenetic associations between CYP and all major antiretrovirals, as well as the importance of these associations...
May 18, 2018: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/29757018/a-current-structural-perspective-on-pxr-and-car-in-drug-metabolism
#17
Cameron D Buchman, Sergio C Chai, Taosheng Chen
Pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) are two members of the nuclear receptor superfamily that play major roles in the expression of various drug metabolism enzymes and are known for their ligand promiscuity. As with other nuclear receptors, PXR and CAR are each composed of a ligand-binding domain (LBD) and a DNA-binding domain (DBD) connected by a hinge region. Areas covered: This review focuses on the information obtained over the last 15+ years from X-ray crystallography studies of the structure of PXR and CAR...
May 14, 2018: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/29746174/developmental-regulation-of-kidney-and-liver-slc-and-abc-drug-transporters-and-drug-metabolizing-enzymes-the-role-of-remote-organ-communication
#18
Jeremiah D Momper, Sanjay K Nigam
The ontogeny of drug transport and metabolism is generally studied independently in tissues, yet in the immediate postnatal period the developmental regulation of transporters and metabolizing enzymes must be coordinated. Using the Remote Sensing and Signaling Hypothesis as a framework, we describe how a systems physiology view helps to make sense of how inter-organ communication via hepatic, renal, and intestinal transporters and drug metabolizing (DMEs) enzymes is regulated from the immediate postnatal period through adulthood...
May 10, 2018: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/29806953/pediatric-physiology-in-relation-to-the-pharmacokinetics-of-monoclonal-antibodies
#19
Paul Malik, Andrea Edginton
Dose design for pediatric trials with monoclonal antibodies (mAbs) is often extrapolated from the adult dose according to weight, age, or body surface area. While these methods account for the size differences between adults and children, they do not account for the maturation of processes that may play a key role in the pharmacokinetics and/or pharmacodynamics of mAbs. With the same weight-based dose, infants and young children typically receive lower plasma exposures when compared to adults. Areas covered: The mechanistic features of mAb distribution, elimination, and absorption are explored in detail and literature-based hypotheses are generated to describe their age-dependence...
June 2018: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/29804481/clinical-reappraisal-of-the-influence-of-drug-transporter-polymorphisms-in-epilepsy
#20
Azzurra Orlandi, Maria Chiara Paolino, Pasquale Striano, Pasquale Parisi
Although novel antiepileptic drugs (AEDs) have been recently released, the issue of drug resistance in epileptic patients remains unsolved and largely unpredictable. Areas covered: We aim to assess the clinical impact of genetic variations that may influence the efficacy of medical treatment in epilepsy patients. Indeed, many genes, including genes encoding drug transporters (ABCB1), drug targets (SCN1A), drug-metabolizing enzymes (CYP2C9, CYP2C19), and human leucocyte antigen (HLA) proteins, may regulate the mechanisms of drug resistance in epilepsy...
May 2018: Expert Opinion on Drug Metabolism & Toxicology
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