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Flavia Storelli, Caroline Samer, Jean-Luc Reny, Jules Desmeules, Youssef Daali
Drug pharmacokinetics (PK) is influenced by multiple intrinsic and extrinsic factors, among which concomitant medications are responsible for drug-drug interactions (DDIs) that may have a clinical relevance, resulting in adverse drug reactions or reduced efficacy. The addition of intrinsic factors affecting cytochromes P450 (CYPs) activity and/or expression, such as genetic polymorphisms and diseases, may potentiate the impact and clinical relevance of DDIs. In addition, greater variability in drug levels and exposures has been observed when such intrinsic factors are present in addition to concomitant medications perpetrating DDIs...
April 17, 2018: Clinical Pharmacokinetics
Shenghui Mei, Weixing Feng, Leting Zhu, Xingang Li, Yazhen Yu, Weili Yang, Baoqin Gao, Xiaojuan Wu, Fang Fang, Zhigang Zhao
PURPOSE: Valproic acid (VPA) is an important drug in seizure control with great inter-individual differences in metabolism and treatment effect. This study aims to identify the effects of genetic variants on VPA clearance in a population pharmacokinetic (popPK) model in children with epilepsy. METHODS: A total of 325 VPA plasma concentrations from 290 children with epilepsy were used to develop the popPK model by using the nonlinear mixed-effects modeling method...
April 17, 2018: European Journal of Clinical Pharmacology
Zhenhai Shang, Feifei Han, Xueyan Zhou, Zejun Bao, Jing Zhu, Tao Wang, Qian Lu, Lei Du, Wei Li, Dongmei Lv, Xiaoxing Yin
Post-Market Research We aimed to investigate the impact of G protein-coupled receptor kinase 5 (GRK5) rs10886471 polymorphism on repaglinide efficacy in Chinese patients with type 2 diabetes mellitus (T2DM). A total of 300 T2DM patients and 210 healthy controls were genotyped for GRK5 rs10886471 on a three-dimensional polyacrylamide gel-based DNA microarray. Eighty-five patients with the same genotypes of cytochrome P450 (CYP) 2C8*3 139Arg and organic anion-transporting polypeptide 1B1 (OATP1B1) 521TT were randomly selected to orally take repaglinide for eight consecutive weeks...
April 16, 2018: Drug Development Research
Jincheng Yang, Maulik Patel, Mina Nikanjam, Edmund V Capparelli, Shirley M Tsunoda, Howard E Greenberg, Scott R Penzak, S Aubrey Stoch, Joseph S Bertino, Anne N Nafziger, Joseph D Ma
Midazolam is the preferred probe to phenotype cytochrome P450 (CYP) 3A activity. This study evaluated a single-concentration, midazolam limited sampling strategy utilizing a population pharmacokinetic (PK) approach to estimate area under the curve, and thus CYP3A activity. Midazolam concentrations from adults during CYP3A constitutive conditions were obtained from previous studies after single, oral or intravenous administration. Population PK modeling was conducted by nonlinear mixed-effects modeling. Potential covariates of clearance, volume of distribution, and bioavailability were evaluated...
April 17, 2018: Journal of Clinical Pharmacology
Tae Yeon Kong, Soon-Sang Kwon, Jae Chul Cheong, Hee Seung Kim, Jin Young Kim, Hye Suk Lee
EAM-2201, a synthetic cannabinoid, is a potent agonist of the cannabinoid receptors that is widely abused as an illicit recreational drug in combination with other drugs. To evaluate the potential of EAM-2201 as a perpetrator of drug–drug interactions, the inhibitory effects of EAM-2201 on major drug-metabolizing enzymes, cytochrome P450s (CYPs) and uridine 5′-diphospho-glucuronosyltransferases (UGTs) were evaluated in pooled human liver microsomes using liquid chromatography–tandem mass spectrometry (LC-MS/MS)...
April 16, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Unji Lee, Mi Hye Kwon, Hee Eun Kang
1. Plasma lipid profile abnormalities in hyperlipidemia can potentially alter the pharmacokinetics of a drug in a complex manner. To evaluate these pharmacokinetic alterations in hyperlipidemia and to determine the underlying mechanism(s), poloxamer 407-induced hyperlipidemic rats (HL rats), a well-established animal model of hyperlipidemia have been used. 2. In this review, we summarize findings on the pathophysiological and gene expression changes in drug-metabolizing enzymes and transporters in HL rats. We discuss pharmacokinetic changes in drugs metabolized primarily via hepatic cytochrome P450 (CYPs) in terms of alterations in hepatic intrinsic clearance (CL'int ), free fraction in plasma (fu ), and hepatic blood flow rate (QH ), depending on the hepatic excretion ratio, as well as drugs eliminated primarily by mechanisms other than hepatic CYPs...
April 16, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Keon Mook Seong, Brad S Coates, May R Berenbaum, John M Clark, Barry R Pittendrigh
BACKGROUND: Cytochrome P450 monooxygenases (P450s) are involved in the biosynthesis of endogenous intracellular compounds and the metabolism of xenobiotics, including chemical insecticides. We investigated the structural and expression level variance across all P450 genes with respect to the evolution of insecticide resistance under multigenerational DDT selection. RESULTS: RNA-seq and reverse transcriptase quantitative PCR indicated that the transcript levels of seven P450 genes were significantly up-regulated and three P450 genes were down-regulated in the DDT-resistant strain 91-R, as compared to the control strain 91-C...
April 15, 2018: Pest Management Science
Meng Li, Qiong Wu, Qiangwei Wang, Dandan Xiang, Guonian Zhu
In aquatic environment, the presence of nanoparticles (NPs) has been reported to modify the bioavailability and toxicity of the organic toxicants. Nevertheless, the combined toxicity of NPs and the pesticides that were used world-widely still remains unclear. Cypermethrin (CYP), a synthetic pyrethroid insecticide, is commonly used for controlling agricultural and indoor pests. Therefore, the effects of titanium dioxide NPs (nTiO2 ) on CYP bioconcentration and its effects on the neuronal development in zebrafish were investigated in our study...
March 31, 2018: Aquatic Toxicology
Rebekka Thøgersen, Bjørn Petrat-Melin, Galia Zamaratskaia, Kai Grevsen, Jette Feveile Young, Martin Krøyer Rasmussen
The physiological effects of the Stevia-derived compounds, rebaudioside A, stevioside and steviol have been the focus of several studies due to their use as sweeteners in food. Despite that, little is known about their potential food-drug interactions. In the present study, IPEC-J2 cells and primary hepatocytes were used to investigate the effect of rebaudioside A, stevioside and steviol on cytochrome p450 (CYP) mRNA expression. Moreover, hepatic microsomes were used to investigate direct interactions between the compounds and specific CYP activity...
August 30, 2018: Food Chemistry
Gabriela Dovrtelova, Ondrej Zendulka, Kristyna Noskova, Jan Jurica, Ondrej Pes, Jan Dusek, Alejandro Carazo, Iveta Zapletalova, Natasa Hlavacova, Petr Pavek
The endocannabinoid system is important for many physiological and pathological processes, but its role in the regulation of liver cytochromes P450 (CYPs) is still unknown. We studied the influence of the endocannabinoid oleamide on rat and human liver CYPs. Oleamide was administered i.p. to rats at doses of 0.1, 1 and 10 mg/kg/day for 7 days. The content and activity of key CYPs was evaluated in rat liver microsomes. Moreover, its interactions with nuclear receptors regulating CYP genes and serum levels of their ligands (prolactin, corticosterone, and free triiodothyronine) were tested in vitro CYP inhibition assays...
April 12, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Diana Busch, Anja Fritz, Lars Ivo Partecke, Claus-Dieter Heidecke, Stefan Oswald
Many orally administered drugs are subject to first-pass metabolism by cytochrome P450 (CYP) enzymes and uridine 5'-diphospho-glucuronosyltransferases (UGT). While their hepatic activity is well characterized, respective information about the intestine are very scare due to limited availability of tissue, very low microsomal protein content and the heterogeneity of the individual segments. As a consequence, determination of enzyme kinetic parameters is challenging. It was therefore the aim of this study to develop a sensitive liquid chromatography tandem mass spectrometry method for the simultaneous quantification of CYP and UGT metabolites formed by clinically relevant intestinal biotransformation enzymes: 4-hydroxydiclofenac (CYP2C9), 5-hydroxyomeprazole (CYP2C19), dextrorphan (CYP2D6), 1-hydroxymidazolam (CYP3A), ezetimibe glucuronide (UGT1A) and naloxone glucuronide (UGT2B7)...
April 5, 2018: Journal of Pharmaceutical and Biomedical Analysis
Marie Stiborová, Helena Dračínská, Lucie Bořek-Dohalská, Zuzana Klusoňová, Jana Holecová, Markéta Martínková, Heinz H Schmeiser, Volker M Arlt
Endocrine disruptors (EDs) are compounds that interfere with the balance of the endocrine system by mimicking or antagonising the effects of endogenous hormones, by altering the synthesis and metabolism of natural hormones, or by modifying hormone receptor levels. The synthetic estrogen 17α-ethinylestradiol (EE2) and the environmental carcinogen benzo[a]pyrene (BaP) are exogenous EDs whereas the estrogenic hormone 17β-estradiol is a natural endogenous ED. Although the biological effects of these individual EDs have partially been studied previously, their toxicity when acting in combination has not yet been investigated...
April 9, 2018: Toxicology
Kristine Hole, Birgit M Wollmann, Camilla Nguyen, Tore Haslemo, Espen Molden
BACKGROUND: Enzyme-inducing antiepileptic drugs (EIAEDs) are among the clinically most important inducers of cytochrome P450 (CYP) 3A4, but there is limited evidence regarding the comparative potency of each EIAED in raising CYP3A4 activity. The aim of this study was to estimate CYP3A4-inductive potency of EIAEDs by comparing CYP3A4 activity in patients treated with carbamazepine, phenobarbital, or phenytoin. METHODS: Residual serum samples from patients treated with EIAEDs or levetiracetam were collected from a therapeutic drug monitoring service for analysis of 4β-hydroxycholesterol (4βOHC), which is an indicator of CYP3A4 activity...
April 11, 2018: Therapeutic Drug Monitoring
Kazuki Nakagita, Kyoichi Wada, Yuka Terada, Sachi Matsuda, Nobue Terakawa, Akira Oita, Mitsutaka Takada
OBJECTIVE: Everolimus is an inhibitor of the mammalian target of rapamycin (mTOR) and has been used in combination with calcineurin inhibitors (tacrolimus and cyclosporine) to prevent allograft rejection following organ transplantation. In heart transplant recipients, everolimus should be maintained at a target blood concentration of 3 - 8 ng/mL, in combination with reduced-dose calcineurin inhibitors and therefore, requires strict monitoring. Fluconazole, an azole antifungal agent, affects blood concentration of tacrolimus by inhibiting the cytochromes P450 (CYP) 3A4 and 3A5...
April 12, 2018: International Journal of Clinical Pharmacology and Therapeutics
Kai Liao, Yong Liu, Chun-Zhi Ai, Xi Yu, Wei Li
OBJECTIVE: Therapeutic response to phenytoin (PHT), a first-line antiepileptic drug (AED), is highly variable, in part likely due to genetic factors. Genetic polymorphisms in cytochrome P450 (CYP) 2C9 and CYP2C19 are expected to affect the metabolism of PHT and consequently affect its maintenance doses. We aimed to clarify the effects of genetic polymorphisms in both enzymes on daily PHT maintenance dosage in Asian epileptic patients by meta-analysis. MATERIALS AND METHODS: A systematic literature search was conducted in PubMed and EMBASE for relevant studies published prior to April 14, 2017...
April 9, 2018: International Journal of Clinical Pharmacology and Therapeutics
Ling Song, Yi Zhang, Ji Jiang, Shuang Ren, Li Chen, Dongyang Liu, Xijing Chen, Pei Hu
AIM: The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model for sinogliatin (HMS-5552, dorzagliatin) by integrating allometric scaling (AS), in vitro to in vivo exploration (IVIVE), and steady-state concentration-mean residence time (Css -MRT) methods and to provide mechanistic insight into its pharmacokinetic properties in humans. METHODS: Human major pharmacokinetic parameters were analyzed using AS, IVIVE, and Css -MRT methods with available preclinical in vitro and in vivo data to understand sinogliatin drug metabolism and pharmacokinetic (DMPK) characteristics and underlying mechanisms...
April 6, 2018: Clinical Pharmacokinetics
Irina V Haidukevich, Tatsiana A Sushko, Anastasia M Tumilovich, Irina P Grabovec, Sergey A Usanov, Andrei A Gilep
CYP2C9 plays a major role in drug metabolism. It is highly polymorphic and among the variants, CYP2C9*2 and CYP2C9*3 have been known to encode the protein with moderately to markedly reduced catalytic activity. Azole antifungals are among the most frequently used drugs in human pharmacotherapy and represent a widely used class of pesticides to which humans are inevitably exposed. Due to the similarities in CYP organization throughout species, azoles can interact not only with the target fungal CYP51 substrate-binding site but can also modulate the catalytic activity of human cytochrome P450s, including CYP2C9, causing severe adverse effects...
April 2, 2018: Toxicology in Vitro: An International Journal Published in Association with BIBRA
María Cecilia García-Espiñeira, Lesly Patricia Tejeda-Benítez, Jesus Olivero-Verbel
Bisphenol A (BPA) is a ubiquitous plasticizer which is absorbed by ingestion and dermal contact; propyl paraben (PPB) inhibits the microbiome and extends the shelf life of many personal care products, whereas triclosan (TCS) is commonly found in antiseptics, disinfectants, or additives. In this work, Caenorhabditis elegans was used as a biological model to assess the toxic effects of BPA, PPB, and TCS. The wild type strain, Bristol N2, was used in bioassays with the endpoints of lethality, growth, and reproduction; green fluorescent protein (GFP) transgenic strains with the hsp-3 , hsp-4 , hsp-16...
April 5, 2018: International Journal of Environmental Research and Public Health
Elvis O Ameyaw, Kodwo B Asmah, Robert P Biney, Isaac T Henneh, Phyllis Owusu-Agyei, James Prah, Arnold D Forkuo
BACKGROUND: Increasing resistance to current anti-malarial therapies requires a renewed effort in searching for alternative therapies to combat this challenge, and combination therapy is the preferred approach to address this. The present study confirms the anti-plasmodial effects of two compounds, cryptolepine and xylopic acid and the relationship that exists in their combined administration determined. METHODS: Anti-plasmodial effect of cryptolepine (CYP) (3, 10, 30 mg kg-1 ) and xylopic acid (XA) (3, 10, 30 mg kg-1 ) was evaluated in Plasmodium berghei-infected male mice after a 6-day drug treatment...
April 4, 2018: Malaria Journal
C Gade, K Dalhoff, T S Petersen, T Riis, C Schmeltz, E Chabanova, H R Christensen, G Mikus, J Burhenne, J C Holm, H Holst
INTRODUCTION: In obese adults Cytochrome P450 (CYP) 2E1 activity is induced, probably due to nonalcoholic fatty liver disease (NALFD), diabetes or hyperlipidemia. CYP2E1 has never been investigated in children with obesity. Pathophysiological changes related to obesity may be different or not as pronounced in children as in adults. Therefore, the pharmacokinetic changes may not be extrapolated into this population. AIM: To test the in vivo activity of CYP2E1 in obese children vs...
April 4, 2018: British Journal of Clinical Pharmacology
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