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S Khalilieh, A Hussain, D Montgomery, V Levine, P M Shaw, I Bodrug, L Mekokishvili, C Bailey-Smith, X S Glasgow, A Cheng, M Martinho, M Iwamoto
AIMS: Tildrakizumab, an interleukin (IL)-23 inhibitor, is indicated for the treatment of moderate to severe chronic plaque psoriasis. Although tildrakizumab is not metabolized by, and does not alter, cytochrome P450 (CYP) expression in vitro, clinically-significant pharmacokinetic effects through changes in systemic inflammation, which alters CYP metabolism, have been well documented. At the time of study conduct, the effect of modulation of inflammation/cytokines, including IL-23 inhibition with tildrakizumab, on CYP metabolism, and therefore the potential for disease-drug interactions, in psoriasis patients was unknown...
June 21, 2018: British Journal of Clinical Pharmacology
J Lv, F Liu, N Feng, X Sun, J Tang, L Xie, Y Wang
BACKGROUND: Pain is one of the major adverse clinical outcomes of cesarean section (CS). In the past few years, researchers and physicians have been optimizing post-operative analgesic modalities, but the results are still undesirable for the parturient. The cytochrome P-450 3A4 (CYP3A4) gene has been reported to contribute significantly to human liver microsomal oxidation of sufentanil and alfentanil. METHODS: We detected the frequency of CYP3A4 mutant allele, which is associated with the metabolism of diverse drugs, including opioids used for anesthesia...
June 21, 2018: Acta Anaesthesiologica Scandinavica
Dae-Seop Shin, Hyewon Seo, Jung Yoon Yang, Jeongmin Joo, So Hee Im, Seong Soon Kim, Sang Kyum Kim, Myung Ae Bae
Predicting drug-drug interactions (DDIs) is an important step during drug development to avoid unexpected side effects. Cytochrome P450 (CYP) 3A4 is the most abundant human hepatic phase I enzyme, which metabolizes >50% of therapeutic drugs. Therefore, it is essential to test the potential of a drug candidate to induce CYP3A4 expression or inhibit its activity. Recently, 3-dimensional (3-D) mammalian cell culture models have been adopted in drug discovery research to assess toxicity, DDIs, and pharmacokinetics...
January 1, 2018: International Journal of Toxicology
Hu Liu, Ye Tian, Kyungae Lee, Pranav Krishnan, May Kwang-Mei Wang, Sean Whelan, Emily Mevers, Veronica Soloveva, Benjamin Dedic, Xinyong Liu, James Cunningham
Previous studies identified an adamantane dipeptide piperazine 3.47 that inhibits Ebola virus (EBOV) infection by targeting the essential receptor Niemann-Pick C1 (NPC1). The physicochemical properties of 3.47 limit its potential for testing in vivo. Optimization by improving potency, reducing hydrophobicity, and replacing labile moieties, identified 3.47 derivatives with improved in-vitro ADME properties that are also highly active against EBOV infection, including when tested in the presence of 50% normal human serum (NHS)...
June 19, 2018: Journal of Medicinal Chemistry
Ya-Bin Yu, Yan Song, Ya Chen, Feng Zhang, Fu-Zhen Qi
Mesenchymal stem cells (MSCs) are considered to be an ideal source for the cell therapy of end‑stage liver diseases. Umbilical cord (UC)‑MSCs can be obtained via a non‑invasive procedure and can be easily cultured, making them potentially superior candidates for cell transplantation when compared with MSCs from other sources. In the present study, UC‑MSCs were induced to differentiate into hepatocytes and were compared with bone marrow (BM)‑MSCs for their hepatic differentiation potential. UC‑MSCs showed significantly higher proliferation than BM‑MSCs...
June 18, 2018: Molecular Medicine Reports
K K Lemberg, T E Heiskanen, M Neuvonen, V K Kontinen, P J Neuvonen, M-L Dahl, E A Kalso
Oxycodone is a strong opioid and it is increasingly used in the management of acute and chronic pain. The pharmacodynamic effects of oxycodone are mainly mediated by the μ-opioid receptor. However, its affinity for the μ-opioid receptor is significantly lower compared with that of morphine and it has been suggested that active metabolites may play a role in oxycodone analgesia. Oxycodone is mainly metabolized by hepatic cytochrome (CYP) enzymes 2D6 and 3A4. Oxycodone is metabolized to oxymorphone, a potent μ-opioid receptor agonist by CYP2D6...
December 29, 2017: Scandinavian Journal of Pain
Tomáš Smutný, Riina Harjumäki, Liisa Kanninen, Marjo Yliperttula, Petr Pávek, Yan-Ru Lou
Herbal medicines have been increasingly used in the last three decades. Despite their popularity, safety issues with herbal products need to be addressed. We performed a feasibility study of the toxic responses of human induced pluripotent stem cell-derived hepatocytes (iHep cells) to phytochemicals in comparison with hepatoblasoma-derived HepG2 cells and long-term human hepatocytes (LTHHs). The iHep cells expressed typical hepatocyte markers cytochrome P450 3A4 (CYP3A4), hepatocyte nuclear factor 4α, and albumin despite the expression of immature markers α-fetoprotein and cytokeratin 19...
June 11, 2018: Toxicology in Vitro: An International Journal Published in Association with BIBRA
Laureen A Lammers, Roos Achterbergh, Johannes A Romijn, Ron A A Mathôt
BACKGROUND AND OBJECTIVES: Previous studies have shown that nutritional status can alter drug metabolism which may result in treatment failure or untoward side effects. This study assesses the effect of two nutritional conditions, short-term fasting, and a short-term high fat diet (HFD) on cytochrome P450 3A4 (CYP3A4) and uridine 5'-diphospho-glucuronosyltransferase (UGT) mediated drug metabolism by studying the pharmacokinetics of midazolam and its main metabolites. METHODS: In a randomized-controlled cross-over trial, nine healthy subjects received a single intravenous administration of 0...
June 6, 2018: European Journal of Drug Metabolism and Pharmacokinetics
Gareth K Jennings, Mei-Hui Hsu, Lisa S Shock, Eric F Johnson, John C Hackett
Cytochrome P450 4B1 (4B1) functions in both xenobiotic and endobiotic metabolism. An ester linkage between Glu-310 in 4B1 and the 5-methyl group of heme facilitates preferential hydroxylation of terminal (ω) methyl groups of hydrocarbons (HCs) and fatty acids compared with ω-1 sites bearing weaker C-H bonds. This preference is retained albeit diminished 4-fold for the E310A mutant, but the reason for this is unclear. Here, a crystal structure of the E310A-octane complex disclosed that noncovalent interactions maintain heme deformation in the absence of the ester linkage...
June 1, 2018: Journal of Biological Chemistry
Gracia M Amaya, Rebecca Durandis, David S Bourgeois, James A Perkins, Arsany A Abouda, Kahari J Wines, Mohamed Mohamud, Samuel A Starks, R Nathan Daniels, Klarissa D Jackson
Sunitinib is a multi-targeted tyrosine kinase inhibitor associated with idiosyncratic hepatotoxicity. The mechanisms of this toxicity are unknown. We hypothesized that sunitinib undergoes metabolic activation to form chemically reactive, potentially toxic metabolites, which may contribute to development of sunitinib-induced hepatotoxicity. The purpose of this study was to define the role of cytochrome P450 (P450) enzymes in sunitinib bioactivation. Metabolic incubations were performed using individual recombinant P450s, human liver microsomal fractions, and P450-selective chemical inhibitors...
May 31, 2018: Chemical Research in Toxicology
Aileen Scheibner, Rory Remmel, David Schladt, William Oetting, Weihua Guan, Baolin Wu, Casey Dorr, Ajay Israni, Pamala A Jacobson
Cytochrome P450 3A5 (CYP3A5) and cytochrome P450 3A4 (CYP3A4) are the predominate enzymes responsible for tacrolimus metabolism. The presence of CYP3A4 and CYP3A5 genetic variants significantly affects tacrolimus clearance and dose requirements. CYP3A5*3 is a loss-of-function variant resulting in no CYP3A5 enzyme production. CYP3A4*22 is a variant that reduces production of functional CYP3A4 protein. Caucasians commonly carry these variant alleles, but very rarely carry all four variant alleles. This report describes four kidney transplant recipients who carry a rare genotype combination (CYP3A5*3/*3 and CYP3A4*22/*22)...
May 26, 2018: Pharmacotherapy
Carlyn Rose C Tan, Saif Abdul-Majeed, Brittany Cael, Stefan K Barta
Proteasome inhibitors disrupt multiple pathways in cells and the bone marrow microenvironment, resulting in apoptosis and inhibition of cell-cycle progression, angiogenesis, and proliferation. Bortezomib is a first-in-class proteasome inhibitor approved for the treatment of multiple myeloma and mantle cell lymphoma after one prior therapy. It is also effective in other plasma cell disorders and non-Hodgkin lymphomas. The main mechanism of action of bortezomib is to inhibit the chymotrypsin-like site of the 20S proteolytic core within the 26S proteasome, thereby inducing cell-cycle arrest and apoptosis...
May 26, 2018: Clinical Pharmacokinetics
Ingolf Cascorbi
Immunosuppressive drugs are a prerequisite in organ transplantation to prevent rejection and are also widely used in inflammatory diseases such as inflammatory bowel disease (IBD) or also in some hematologic malignancies-depending on the mode of action. For thiopurine analogs the polymorphic thiopurine S-methyltransferase (TPMT) was early detected to be associated with thiopurine-induced leukopenia; recent studies identified also NUDT15 to be related to this severe side effect. For drugs like methotrexate and mycophenolate mofetil a number of ADME genes like UDP-glucuronosyltransferases (UGTs) and ABC efflux transporters were investigated, however, with partly contradicting results...
2018: Advances in Pharmacology
Roland Heinig, Michael Gerisch, Anna Engelen, Johannes Nagelschmitz, Stephanie Loewen
BACKGROUND AND OBJECTIVES: Finerenone is a selective, non-steroidal mineralocorticoid receptor antagonist. In vivo and in vitro studies were performed to assess absolute bioavailability of finerenone, the effect of metabolic enzyme inhibitors on the pharmacokinetics of finerenone and its metabolites, the quantitative contribution of the involved enzymes cytochrome P450 (CYP) 3A4 and CYP2C8 and the relevance of gut wall versus liver metabolism. METHODS: The pharmacokinetics, safety and tolerability of finerenone (1...
May 19, 2018: European Journal of Drug Metabolism and Pharmacokinetics
Xiang Li, Youjun Xu, Luhua Lai, Jianfeng Pei
Adverse side effects of drug-drug interactions induced by human cytochrome P450 (CYP450) inhibition is an important consideration in drug discovery. It is highly desirable to develop computational models that can predict the inhibitive effect of a compound against a specific CYP450 isoform. In this study, we developed a multi-task model for concurrent inhibition prediction of five major CYP450 isoforms, namely 1A2, 2C9, 2C19, 2D6, and 3A4. The model was built by training multi-task autoencoder deep neural network (DNN) on a large dataset containing more than 13000 compounds, extracted from PubChem BioAssay Database...
May 18, 2018: Molecular Pharmaceutics
Jorge Guzman-Lepe, Eduardo Cervantes-Alvarez, Alexandra Collin de l'Hortet, Yang Wang, Wendy M Mars, Yoshinao Oda, Yuki Bekki, Masahiro Shimokawa, Huanlin Wang, Tomoharu Yoshizumi, Yoshihiko Maehara, Aaron Bell, Ira J Fox, Kazuki Takeishi, Alejandro Soto-Gutierrez
The mechanisms by which the liver fails in end-stage liver disease remain elusive. Disruption of the transcription factor network in hepatocytes has been suggested to mediate terminal liver failure in animals. However, this hypothesis remains unexplored in human subjects. To study the relevance of transcription factor expression in terminal stages of chronic liver failure in humans, we analyzed the expression of liver-enriched transcription factors (LETFs) hepatocyte nuclear factor (HNF)4α, HNF1α, forkhead box protein A2 (FOXA2), CCAAT/enhancer-binding protein (CEBP)α, and CEBPβ...
May 2018: Hepatology Communications
Fabio Bachmann, Urs Duthaler, Deborah Rudin, Stephan Krähenbühl, Manuel Haschke
Metamizole is an old analgesic used frequently in some countries. Active metabolites of metamizole are the non-enzymatically generated N-methyl-4-aminoantipyrine (4-MAA) and its demethylation product 4-aminoantipyrine (4-AA). Previous studies suggested that 4-MAA demethylation can be performed by hepatic cytochrome P450 (CYP) 3A4, but the possible contribution of other CYPs remains unclear. Using human liver microsomes (HLM), liver homogenate and HepaRG cells, we could confirm 4-MAA demethylation by CYPs. Based on CYP induction (HepaRG cells) and CYP inhibition (HLM) we could identify CYP2B6, 2C8, 2C9 and 3A4 as major contributors to 4-MAA demethylation...
May 8, 2018: European Journal of Pharmaceutical Sciences
Haitham AlRabiah, Abdul Ahad, Gamal A E Mostafa, Fahad I Al-Jenoobi
BACKGROUND AND OBJECTIVE: Cytochrome P450 (CYP) 1A2, 2C9, 2D6, and 3A4 are the most important phase I drug-metabolizing enzymes in the liver, but there is a dearth of literature available on the effects of naltrexone hydrochloride on these major enzymes present in the human liver. Thus, in the present study, the effect of naltrexone hydrochloride on the activity of CYP1A2, 2C9, 2D6, and 3A4 using human liver microsomes (HLM) was investigated. METHODS: A selective probe for CYP1A2, 2C9, 2D6, and 3A4 was incubated with HLM with or without naltrexone hydrochloride...
May 9, 2018: European Journal of Drug Metabolism and Pharmacokinetics
Kalyanashis Jana, Tusar Bandyopadhyay, Bishwajit Ganguly
The efficacy of S-omeprazole as proton pump inhibitor compared to its enantiomer R-omeprazole is studied using density functional theoretical calculations. The pharmacokinetic studies suggest that the efficacy of S-omeprazole presumably depends on metabolic pathway and excretion from the human body. The DFT calculations at SMDWater -B3LYP-D3/6-311+G(d,p)/LANL2DZ//B3LYP/6-31G(d)/LANL2DZ with triradicaloid model active species, [Por•+ FeIV (SH)O], of the CYP2C19 enzyme with high spin quartet and low spin doublet states demonstrate C-H bond activation mechanism through a two-state rebound process for hydroxylation of R-omeprazole and S-omeprazole...
May 9, 2018: Journal of Physical Chemistry. B
David N Franz, John A Lawson, Zuhal Yapici, Christian Brandt, Michael H Kohrman, Michael Wong, Mathieu Milh, Adelheid Wiemer-Kruel, Maurizio Voi, Neva Coello, Wing Cheung, Kai Grosch, Jacqueline A French
OBJECTIVE: The present analysis examined the exposure-response relationship by means of the predose everolimus concentration (Cmin ) and the seizure response in patients with tuberous sclerosis complex-associated seizures in the EXIST-3 study. Recommendations have been made for the target Cmin range of everolimus for therapeutic drug monitoring (TDM) and the doses necessary to achieve this target Cmin . METHODS: A model-based approach was used to predict patients' daily Cmin ...
May 4, 2018: Epilepsia
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