Sunjoo Kim, Dong Kyun Kim, Yongho Shin, Ji-Hyeon Jeon, Im-Sook Song, Hye Suk Lee
AB-FUBINACA, a synthetic indazole carboxamide cannabinoid, has been used worldwide as a new psychoactive substance. Because drug abusers take various drugs concomitantly, it is necessary to explore potential AB-FUBINACA-induced drug-drug interactions caused by modulation of drug-metabolizing enzymes and transporters. In this study, the inhibitory effects of AB-FUBINACA on eight major human cytochrome P450s (CYPs) and six uridine 5'-diphospho-glucuronosyltransferases (UGTs) of human liver microsomes, and on eight clinically important transport activities including organic cation transporters (OCT)1 and OCT2, organic anion transporters (OAT)1 and OAT3, organic anion transporting polypeptide transporters (OATP)1B1 and OATP1B3, P-glycoprotein, and breast cancer resistance protein (BCRP) in transporter-overexpressing cells were investigated...
October 8, 2020: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Kimberly Lapham, Ernesto Callegari, Julie Cianfrogna, Jian Lin, Mark Niosi, Christine C Orozco, Raman Sharma, Theunis C Goosen
Ertugliflozin is primarily cleared through UDP‑glucurosyltransferase (UGT)-mediated metabolism (86%) with minor oxidative clearance (12%). In vitro phenotyping involved enzyme kinetic characterization of UGTs or cytochrome P450 (CYP) enzymes catalyzing formation of the major 3- O -β-glucuronide (M5c) and minor 2- O -β-glucuronide (M5a), monohydroxy-ertugliflozin (M1 and M3), and des-ethyl ertugliflozin (M2) metabolites in human liver microsomes (HLM). Fractional clearance (fCL ) estimated from HLM intrinsic clearance (CLint ) indicated a major role for glucuronidation (fCL 0...
October 5, 2020: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Marie-Lynn Cuypers, Hugues Chanteux, Eric Gillent, Pierre Bonnaillie, Kenneth Saunders, Claire Beckers, Claude Delatour, Sylvie Dell'Aiera, Anna-Lena Ungell, Johan Nicolaï
Early assessment of metabolism pathways of new chemical entities (NCEs) guides the understanding of drug-drug interactions (DDIs). Selective enzyme inhibitors are indispensable in cytochrome P450 (CYP) reaction phenotyping. The most commonly applied CYP2C19 inhibitor, omeprazole, lacks selectivity. Two promising alternatives, (+)-N-3-benzylnirvanol and (-)-N-3-benzylphenobarbital, are already used as CYP2C19 inhibitors in some in vitro studies with suspended human hepatocytes. However, a full validation proving their suitability in terms of CYP and non-CYP selectivity has not been presented in literature...
August 24, 2020: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Chuang-Wei Wang, Wichittra Tassaneeyakul, Chun-Bing Chen, Wei-Ti Chen, Yu-Chuan Teng, Cheng-Yang Huang, Chonlaphat Sukasem, Chun-Wei Lu, Yun-Shien Lee, Siew-Eng Choon, Nontaya Nakkam, Rosaline Chung-Yee Hui, Yen-Hua Huang, Ya-Ching Chang, Yang Yu-Wei Lin, Chee-Jen Chang, Tsu-Man Chiu, Wasun Chantratita, Parinya Konyoung, Chaw-Ning Lee, Jettanong Klaewsongkram, Ticha Rerkpattanapipat, Warayuwadee Amornpinyo, Niwat Saksit, Pawinee Rerknimitr, Huang Yu Huei, Shang-Hong Lin, Chao-Kai Hsu, Wen-Lang Fan, Cheng-Chi Chan, Yu-Jr Lin, Shuen-Iu Hung, Wen-Hung Chung
BACKGROUND: Co-trimoxazole, a sulfonamide antibiotic, is used to treat a variety of infections worldwide, and it remains a common first-line medicine for prophylaxis against Pneumocystis jiroveci pneumonia. However, it can cause severe cutaneous adverse reactions (SCAR), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reactions with eosinophilia and systemic symptoms (DRESS). The pathomechanism of co-trimoxazole-induced SCAR remains unclear. OBJECTIVE: We aimed to investigate the genetic predisposition of co-trimoxazole-induced SCAR...
August 10, 2020: Journal of Allergy and Clinical Immunology
Fabrice A Somé, Thomas Bazié, Hanna Y Ehrlich, Justin Goodwin, Aine Lehane, Catherine Neya, Kabré Zachari, Martina Wade, Jean-Marie Ouattara, Brian D Foy, Roch K Dabiré, Sunil Parikh, Jean-Bosco Ouédraogo
BACKGROUND: Since 2014, seasonal malaria chemoprevention (SMC) with amodiaquine-sulfadoxine-pyrimethamine (AQ-SP) has been implemented on a large scale during the high malaria transmission season in Burkina Faso. This paper reports the prevalence of microscopic and submicroscopic malaria infection at the outset and after the first round of SMC in children under 5 years old in Bama, Burkina Faso, as well as host and parasite factors involved in mediating the efficacy and tolerability of SMC...
July 6, 2020: Malaria Journal
Luiz Carlos da Costa Junior, Clarissa Lourenço de Castro, Daniely Regina Freitas-Alves, Rosane Vianna-Jorge, Paulo Caleb Júnior Lima Santos
BACKGROUND: Paclitaxel/carboplatin combination is the standard chemotherapeutic protocol for gynecologic cancers, but severe toxicities may compromise treatment. There is great inter-individual variability regarding the incidence and severity of toxicities, which may be due to single-nucleotide polymorphisms (SNPs) affecting drug disposition or cellular sensitivity. Here we investigate the impact of selected SNPs in ERCC1, ABCB1, CYP2C8, and CYP3A5 genes on the incidence of severe toxicities, including nephro- and hepatotoxicity...
June 20, 2020: European Journal of Clinical Pharmacology
Mailys De Sousa Mendes, Oliver Hatley, Katherine Linda Gill, Karen Rowland Yeo, Alice Ban Ke
Paclitaxel is the backbone of standard chemotherapeutic regimens used in a number of malignancies and is frequently given with concomitant medications. Newly developed oncolytic agents, including tyrosine kinase inhibitors are often shown to be CYP3A4 and P-gp inhibitors. The aim of this study was to develop a PBPK model for intravenously administered paclitaxel in order to predict the incidence of neutropenia and to estimate the DDI potential as a victim drug. The dose-dependent effects on paclitaxel plasma protein binding, volume of distribution and drug clearance were considered for dose levels of 80 mg/m2 , 135 mg/m2 and 175 mg/m2 ...
May 18, 2020: European Journal of Pharmaceutical Sciences
Thoria Diab, Samar S Alkafaas, Thanaa I Shalaby, Mohamed Hessien
BACKGROUND AND OBJECTIVE: Although the anticancer potentials of water-insoluble drugs are improved by nanoformulation, other intervening factors may contribute in the drug efficacy. This work was designated to explore the effect of paclitaxel-loaded Poly(Lactic-co-Glycolic Acid) (PLGA) nanoparticles on the viability of cancer cells, the expression of Taxol Resistance gene I (TXR1) and paclitaxel metabolizing genes. METHODS: Paclitaxel loaded PLGA Nanoparticles (PTX-NPs) were prepared, physically characterized and used in the treatment of breast adenocarcinoma cells (MCF-7) and hepatoma cells (HepG2)...
2020: Anti-cancer Agents in Medicinal Chemistry
So-Young Park, Phi-Hung Nguyen, Gahyun Kim, Su-Nyeong Jang, Ga-Hyun Lee, Nguyen Minh Phuc, Zhexue Wu, Kwang-Hyeon Liu
Like flavonoids, biflavonoids, dimeric flavonoids, and polyphenolic plant secondary metabolites have antioxidant, antibacterial, antiviral, anti-inflammatory, and anti-cancer properties. However, there is limited data on their effects on cytochrome P450 (P450) and uridine 5'-diphosphoglucuronosyl transferase (UGT) enzyme activities. In this study we evaluate the inhibitory potential of five biflavonoids against nine P450 activities (P450s1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A) in human liver microsomes (HLMs) using cocktail incubation and liquid chromatography-tandem mass spectrometry (LC-MS/MS)...
April 10, 2020: Pharmaceutics
Jeffry Adiwidjaja, Alan V Boddy, Andrew J McLachlan
AIMS: This study aimed to investigate the potential interaction between Schisandra sphenanthera, imatinib and bosutinib combining in vitro and in silico methods. METHODS: In vitro metabolism of imatinib and bosutinib using recombinant enzymes and human liver microsomes were investigated in the presence and absence of Schisandra lignans. PBPK models for the lignans accounting for reversible and mechanism-based inhibitions and induction of CYP3A enzymes were built in the Simcyp Simulator (version 17) and evaluated for their capability to predict interactions with midazolam and tacrolimus...
April 6, 2020: British Journal of Clinical Pharmacology
Thoria Diab, Samar Sami AlKafaas, Thanaa Ibrahim Shalaby, Mohamed Hessien
Although the chemosensitizing effect of Dexamethasone (DEX) and its ability to increase the sensitivity of breast cancer cells to chemotherapy were previously reported, this study aimed to explore how far cotreatment of breast cancer cells with paclitaxel (PTX) and DEX mimics the anticancer effect of nanoformulated PTX. To establish this goal, PTX was nanoformulated with poly (lactic-co-glycolic acid) (PLGA) and the nanoparticles (PTX-NPs) were physically authenticated. Breast cancer cells (MCF-7) were treated with PTX or PTX-NPs in presence or absence of low concentration (10 nM) of DEX...
March 23, 2020: Bioorganic Chemistry
Wenjuan Ma, Wei Wang, Xuhua Huang, Guangzhe Yao, Qi Jia, Jiayuan Shen, Huizi Ouyang, Yanxu Chang, Jun He
Red ginseng is often combined with Aconiti Lateralis Radix Praeparata to reduce alkaloids-related toxicity of the latter. Such herb-pairing also results in better therapeutic effect in heart failure, as compared to the singular use of either herb. The purpose of this study was to investigate the effect of Aconiti Lateralis Radix Praeparata and its combination with red ginseng on the activities of CYP450 enzymes in rats. A sensitive and reliable HPLC-MS/MS method was established and validated for the simultaneous determination of eight probe drugs, phenacetin (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), dapsone (CYP3A4), 7-hydroxycoumarin (CYP2A6), bupropion (CYP2B6), and amodiaquine (CYP2C8), in rat plasma using diazepam as internal standard (IS)...
2020: Evidence-based Complementary and Alternative Medicine: ECAM
Yuuki Akagi, Akiko Iketaki, Haruna Kimura, Yuki Matsudaira, Takami Yoshida, Takahiro Nishimura, Yohei Kawano, Yasunari Mano, Erina Shigematsu, Makoto Ujihara
Background: Repaglinide is widely prescribed to reduce postprandial hyperglycemia and elevated glycated hemoglobin (HbA1c) levels associated with type 2 diabetes, and clopidogrel is a thienopyridine antiplatelet agent and widely used in cardiovascular and cerebrovascular diseases. It has been suggested that the concomitant use of repaglinide with clopidogrel may inhibit repaglinide metabolism, because repaglinide is a substrate of cytochrome P450 2C8 (CYP2C8) and the main metabolite of clopidogrel acyl-β-D-glucuronide inhibits CYP2C8 activity...
2020: Journal of Pharmaceutical Health Care and Sciences
Won-Gu Choi, Ria Park, Dong Kyun Kim, Yongho Shin, Yong-Yeon Cho, Hye Suk Lee
Mertansine, a tubulin inhibitor, is used as the cytotoxic component of antibody-drug conjugates (ADCs) for cancer therapy. The effects of mertansine on uridine 5'-diphospho-glucuronosyltransferase (UGT) activities in human liver microsomes and its effects on the mRNA expression of cytochrome P450s (CYPs) and UGTs in human hepatocytes were evaluated to assess the potential for drug-drug interactions (DDIs). Mertansine potently inhibited UGT1A1-catalyzed SN-38 glucuronidation, UGT1A3-catalyzed chenodeoxycholic acid 24-acyl-β-glucuronidation, and UGT1A4-catalyzed trifluoperazine N -β-d-glucuronidation, with K i values of 13...
March 2, 2020: Pharmaceutics
Mingxiang Liao, Sarah Jaw-Tsai, Jeri Beltman, Andrew D Simmons, Thomas C Harding, Jim J Xiao
The absorption, distribution, metabolism, elimination, and drug-drug interaction (DDI) potential of the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib was characterized in vitro .Rucaparib showed moderate cellular permeability, moderate human plasma protein binding (70.2%), and slow metabolism in human liver microsomes (HLMs). In HLMs, cytochrome P450 (CYP) 1A2 and CYP3A contributed to the metabolism of rucaparib to its major metabolite M324 with estimated fractions of metabolism catalyzed by CYP (fm,CYP) of 0...
March 4, 2020: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
A Licito, G Marotta, M Battaglia, G Benincasa, L Mentone, M R Grillo, V De Lucia, G Leonardi, A Bignucolo, F Comello, R Di Francia, D De Lucia
OBJECTIVE: At present, several strategies for preventing neuromuscular pain in Type 2 Diabetes Mellitus (T2DM) have been investigated. Recently, findings on genetic variants associated with adverse events to statin-based therapy have been reported. The study aimed at measuring whether Pharmacogenomics (PGx) profile can affect neuromuscular pain in patients carrying T2DM and cardiovascular diseases. An extensive panel of 5 polymorphisms on 4 candidate genes, previously validated as significant markers related to Sulphonylureas and Glitinides (SU-G) plus Simvastatin neuromuscular toxicity, is herein analyzed and discussed...
January 2020: European Review for Medical and Pharmacological Sciences
Fabiana Dalla Vecchia Genvigir, Antony Brayan Campos-Salazar, Claudia Rosso Felipe, Helio Tedesco-Silva, José Osmar Medina-Pestana, Sonia de Quateli Doi, Alvaro Cerda, Mario Hiroyuki Hirata, María José Herrero, Salvador Francisco Aliño, Rosario Dominguez Crespo Hirata
Aim: The influence of variants in pharmacokinetics-related genes on long-term exposure to tacrolimus (TAC)-based therapy and clinical outcomes was investigated. Patients & methods: Brazilian kidney recipients were treated with TAC combined with everolimus (n = 178) or mycophenolate sodium (n = 97). The variants in CYP2C8 , CYP2J2 , CYP3A4, CYP3A5 , POR , ABCB1 , ABCC2, ABCG2 , SLCO1B1 and SLCO2B1 were analyzed. Main results: CYP3A5*3/*3 genotype influenced increase in TAC concentration from week 1 to month 6 post-transplantation (p < 0...
January 2020: Pharmacogenomics
Masataka Nakano, Kyoko Ondo, Seiya Takemoto, Tatsuki Fukami, Miki Nakajima
The methylation of adenosines at the N6 position (m6 A formation) is the most prevalent type of RNA modification in humans. This modification is mediated by methyltransferase like the 3 (METTL3)-METTL14 complex, and the methyl group can be removed by RNA demethylases including fat mass and obesity-associated (FTO) and AlkB homolog 5. The formed m6 A is recognized by reader proteins such as members of the YT521-B homology (YTH) family, resulting in changes in the splicing, nuclear export, and decay of RNA or translation...
November 7, 2019: Biochemical Pharmacology
Liuya Wei, Najia Mansoor, Rafeeq Alam Khan, Martin Czejka, Tasneem Ahmad, Mansoor Ahmed, Mohsin Ali, Dong-Hua Yang
Antiretroviral therapy has been the main stay of treatment of neonates born to HIV infected mothers. Neonates born prematurely to HIV positive mothers are underdeveloped not only in anatomical terms but also in their physiological systems. Zidovudine, the first antiretroviral drug in clinical therapy for treatment of HIV has been approved for the use in preterm neonates both prophylactically and therapeutically. The present work shows whole body physiologically based pharmacokinetic (WB-PBPK) WB-PBPK model development for Zidovudine in preterm neonates of varying gestational ages to observe the pharmacokinetic behavior of the drug in this vulnerable group of population...
November 6, 2019: Biopharmaceutics & Drug Disposition
Sonia Mota-Zamorano, Luz M González, Enrique Luna, José J Fernández, Áurea Gómez, Alberto Nieto-Fernández, Nicolás R Robles, Guillermo Gervasini
Cytochrome P450 (CYP) enzymes metabolize arachidonic acid to vasoactive eicosanoids such as epoxyeicosatrienoic acids (EETs) and 20-Hydroxyeicosatetraenoic acid (20-HETE), whilst soluble epoxide hydrolase, encoded by the EPHX2 gene, is in charge of EETs degradation. We aimed to analyze the influence of common, functional polymorphisms in four genes of the donor on the renal biopsy scores independently assigned by pathologists. Additionally, we examined whether this score or the presence of these SNPs were independent risk factors of clinical outcomes in the first year after grafting...
2019: PloS One
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