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Sarah Billington, Laurent Salphati, Cornelis E C A Hop, Xiaoyan Chu, Raymond Evers, Doug Burdette, Christopher Rowbottom, Yurong Lai, Guangqing Xiao, W Griffith Humphreys, Tot Bui Nguyen, Bhagwat Prasad, Jashvant D Unadkat
For in-vitro to in-vivo extrapolation (IVIVE) of brain distribution of drugs that are transported at the human blood-brain barrier (BBB), it's important to quantify the inter-individual and regional variability of drug transporter abundance at this barrier. Therefore, using quantitative targeted proteomics, we compared the abundance of ABC and SLC transporters in brain microvascular endothelial cells (BMEC) isolated from post-mortem specimens of two matched brain regions, the occipital (BA17) and parietal (BA39) lobe, from 30 adults...
January 23, 2019: Clinical Pharmacology and Therapeutics
Charles Awortwe, Henrike Bruckmueller, Ingolf Cascorbi
Although several studies on pharmacokinetic and/or pharmacodynamic herb-drug interactions (HDI) have been conducted in healthy volunteers, there is large uncertainty on the validity of these studies. A qualitative review and a meta-analysis were performed to establish the clinical evidence of these interaction studies. Out of 4026 screened abstracts, 32 studies were included into the qualitative analysis. The meta-analysis was performed on eleven additional studies. St. John's wort (SJW) significantly decreased the AUC (p < 0...
January 17, 2019: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Anna-Katharina Hankele, Stefan Bauersachs, Susanne E Ulbrich
Estrogen metabolism results in the formation of inactive estrogen sulphates and glucuronides. Despite the lack of receptor binding, circulating conjugated estrogens might serve as a reservoir for the active form through the involvement of specific cleaving enzymes. In order to elucidate the potential role that estrogen conjugates play in the regulation of the estrous cycle, we determined the concentration of progesterone, estrogen and estrogen conjugates in serum and endometrial homogenates of cycling gilts...
November 20, 2018: Reproductive Biology
Xiaoxi Lu, Ting Chan, Zhengqi Cheng, Tahiatul Shams, Ling Zhu, Michael Murray, Fanfan Zhou
The Organic Anion Transporting Polypeptides (OATPs) are important membrane proteins that mediate the cellular uptake of drugs and endogenous substances. OATP1A2 is widely distributed in many human tissues that are targeted in drug therapy; defective OATP1A2 leads to altered drug disposition influencing therapeutic outcomes. 5' AMP-activated protein kinase (AMPK) signalling plays an important role in the pathogenesis of the metabolic syndrome characterized by an increased incidence of type II diabetes and non-alcoholic fatty liver disease...
October 22, 2018: Molecular Pharmacology
Anne M Dolberg, Stephan Reichl
With nearly 400 members, the solute-linked carrier (SLC) superfamily is one of the most important gene classes concerning the disposition of drugs and the transport of physiological substrates in the human body. The mapping of related transport proteins is already well advanced for the intestines, kidneys and liver, but it has recently been brought into focus for various respiratory epithelia. The aim of this study was to evaluate the expression of several SLC transporters in differently cultured RPMI 2650 cells, as well as in specimens of the human nasal mucosa...
October 15, 2018: European Journal of Pharmaceutical Sciences
Paola Bukuroshi, Hiroshi Saitoh, Lilia Magomedova, Carolyn L Cummins, Edwin C Chow, Albert P Li, K Sandy Pang
In vitro cell-based assays are common screening tools used for the identification of new VDR ligands. For 25-hydroxyvitamin D3 [25(OH)D3 ] and 1α-hydroxyvitamin D3 [1α(OH)D3 ], protein expressions of CYP2R1 and CYP27B1, respectively, that form the active 1α,25-dihydroxyvitamin D3 [1,25(OH)2 D3 ] ligand were detected in human embryonic kidney (HEK293) cells expressing the GAL4-hVDR, the human brain microvessel endothelial (hCMEC/D3) and adenocarcinoma colonic (Caco-2) cells. The impact of bioactivation enzymes was shown upon the addition of ketoconazole (10 μM KTZ), a pan-CYP inhibitor, which reduced the apparent potency of 25(OH)D3 and increased the EC50 from 272 to 608 nM in HEK293 cells...
September 2018: Biochemical Pharmacology
José Pablo Werba, Shingen Misaka, Monica Gianna Giroli, Kenju Shimomura, Manuela Amato, Niccolò Simonelli, Lorenzo Vigo, Elena Tremoli
Many patients treated with cardiovascular (CV) drugs drink green tea (GT), either as a cultural tradition or persuaded of its putative beneficial effects for health. Yet, GT may affect the pharmacokinetics and pharmacodynamics of CV compounds. Novel GT-CV drug interactions were reported for rosuvastatin, sildenafil and tacrolimus. Putative mechanisms involve inhibitory effects of GT catechins at the intestinal level on influx transporters OATP1A2 or OATP2B1 for rosuvastatin, on CYP3A for sildenafil and on both CYP3A and the efflux transporter p-glycoprotein for tacrolimus...
April 2018: Journal of Food and Drug Analysis
Markus Grube, Paul Hagen, Gabriele Jedlitschky
Neurosteroids, comprising pregnane, androstane, and sulfated steroids can alter neuronal excitability through interaction with ligand-gated ion channels and other receptors and have therefore a therapeutic potential in several brain disorders. They can be formed in brain cells or are synthesized by an endocrine gland and reach the brain by penetrating the blood-brain barrier (BBB). Especially sulfated steroids such as pregnenolone sulfate (PregS) and dehydroepiandrosterone sulfate (DHEAS) depend on transporter proteins to cross membranes...
2018: Frontiers in Pharmacology
Zhaojian Xiang, Weike Li, Lixue Wang, Jicai Yi, Kaiwen Chen, Mei Hong
Organic anion transporting polypeptides (OATPs; gene symbol SLCO ) are membrane transporters that mediate the transport of wide ranges of compounds. The expression of different OATP members has been reported in the kidney, liver, placenta, brain, and intestine. Because of their broad substrate spectra and wide distribution within the human body, these transporters have been proposed to play key roles in the influx transport of many oral drugs. Inflammation is known to regulate the expression and functions of many drug-metabolizing enzymes and drug transporters...
May 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Osamu Abe, Tomoyuki Ono, Hideyuki Sato, Fabian Müller, Hiroshi Ogata, Itaru Miura, Yayoi Shikama, Hirooki Yabe, Satomi Onoue, Martin F Fromm, Junko Kimura, Shingen Misaka
PURPOSE: The aim of the present study is to investigate a possible role of a single dose of (-)-epigallocatechin gallate (EGCG), the major catechin in green tea, for the pharmacokinetic interaction between green tea and nadolol in humans. METHODS: In a randomized three-phase crossover study, 13 healthy volunteers received single doses of 30 mg nadolol orally with water (control), or an aqueous solution of EGCG-concentrated green tea extract (GTE) at low or high dose...
June 2018: European Journal of Clinical Pharmacology
Shu-Mei Wang, Wei-Xin Zeng, Wan-Shui Wu, Lu-Lu Sun, Dan Yan
Organic anion-transporting polypeptide 1A2 (OATP1A2) is involved in the cellular uptake of methotrexate (MTX). Genetic variation in solute carrier organic anion transporter family member 1A2 (SLCO1A2, the coding gene of OATP1A2) has important implications for the elimination of MTX. We investigated the association between a microRNA (miRNA) binding site polymorphism (rs4149009 G > A) in the 3'-untranslated region (3'-UTR) of SLCO1A2 with the serum MTX concentrations in Chinese children with acute lymphoblastic leukemia (ALL)...
February 2018: Leukemia Research
Anna Maria Ingelido, Annalisa Abballe, Simonetta Gemma, Elena Dellatte, Nicola Iacovella, Giovanna De Angelis, Franco Zampaglioni, Valentina Marra, Roberto Miniero, Silvia Valentini, Francesca Russo, Marina Vazzoler, Emanuela Testai, Elena De Felip
In 2013 a contamination of drinking water by perfluoroalkylated substances (PFASs) was discovered in areas of the Veneto Region (northern Italy). In this study the exposure to PFASs of people living in the aforesaid areas was characterized: contaminant serum concentrations were measured and compared with those of a control population group living in neighboring areas at background exposure (based on available drinking water data). The enrolled population was also genotyped for the OATP1A2*3 allelic variant, possibly affecting PFAS excretion and hence the internal dose...
January 2018: Environment International
Lucie Navrátilová, Jana Ramos Mandíková, Petr Pávek, Přemysl Mladěnka, František Trejtnar
1. Some flavonoids contained in the common diet have been shown to interact with important membrane uptake transporters, including organic anion transporting polypeptides (OATPs). OATP2B1 and OATP1A2 expressed in the apical membrane of human enterocytes may significantly contribute to the intestinal absorption of drugs, e.g. statins. This study is aimed at an evaluation of the inhibitory potency of selected food honey flavonoids (namely galangin, myricetin, pinocembrin, pinobanksin, chrysin and fisetin) toward hOATP2B1 and hOATP1A2 as well as at examining their effect on the cellular uptake of the known OATP substrate rosuvastatin...
July 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Xiaozhe Qi, Els Wagenaar, Wentao Xu, Kunlun Huang, Alfred H Schinkel
Ochratoxin A (OTA) is a fungal secondary metabolite that can contaminate various foods. OTA has several toxic effects like nephrotoxicity, hepatotoxicity, and neurotoxicity in different animal species, but its mechanisms of toxicity are still unclear. How OTA accumulates in kidney, liver, and brain is as yet unknown, but transmembrane transport proteins are likely involved. We studied transport of OTA in vitro, using polarized MDCKII cells transduced with cDNAs of the efflux transporters mouse (m)Bcrp, human (h)BCRP, mMrp2, or hMRP2, and HEK293 cells overexpressing cDNAs of the human uptake transporters OATP1A2, OATP1B1, OATP1B3, or OATP2B1 at pH7...
August 15, 2017: Toxicology and Applied Pharmacology
Michelle Kim, Perri Deacon, Rommel G Tirona, Richard B Kim, Christopher L Pin, Henriette E Meyer Zu Schwabedissen, Rennian Wang, Ute I Schwarz
Organic anion-transporting polypeptides (OATPs) are membrane proteins that mediate cellular uptake of structurally diverse endogenous and exogenous compounds, including bile salts, thyroid and sex hormones, pharmacological agents, and toxins. Roles of OATPs in human liver are well established. Our recent report suggested the presence of the hepatic transporter OATP1B3 in human β cells. The aim of this study was to better characterize cellular localization and interindividual variation in OATP1B3 expression in human adult islets as a function of age, sex, and pancreatic disease, and to assess the expression of other OATPs...
October 2017: Histochemistry and Cell Biology
Massoud Saidijam, Fatemeh Karimi Dermani, Sareh Sohrabi, Simon G Patching
1. Efflux proteins at the blood-brain barrier provide a mechanism for export of waste products of normal metabolism from the brain and help to maintain brain homeostasis. They also prevent entry into the brain of a wide range of potentially harmful compounds such as drugs and xenobiotics. 2. Conversely, efflux proteins also hinder delivery of therapeutic drugs to the brain and central nervous system used to treat brain tumours and neurological disorders. For bypassing efflux proteins, a comprehensive understanding of their structures, functions and molecular mechanisms is necessary, along with new strategies and technologies for delivery of drugs across the blood-brain barrier...
May 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Jingjing Yu, Zhu Zhou, Jessica Tay-Sontheimer, René H Levy, Isabelle Ragueneau-Majlessi
In recent years, an increasing number of clinical drug-drug interactions (DDIs) have been attributed to inhibition of intestinal organic anion-transporting polypeptides (OATPs); however, only a few of these DDI results were reflected in drug labels. This review aims to provide a thorough analysis of intestinal OATP-mediated pharmacokinetic-based DDIs, using both in vitro and clinical investigations, highlighting the main mechanistic findings and discussing their clinical relevance. On the basis of pharmacogenetic and clinical DDI results, a total of 12 drugs were identified as possible clinical substrates of OATP2B1 and OATP1A2...
September 2017: Journal of Pharmaceutical Sciences
A C C Costa, E B Coelho, V L Lanchote, B V Correia, J T Abumansur, G R Lauretti, N V de Moraes
PURPOSE: Rocuronium (ROC) is a neuromuscular blocker mainly eliminated by biliary excretion dependent on organic anion transporting polypeptide 1A2 (OATP1A2) hepatocellular uptake. However, the influence of SLCO1A2 (gene encoding OATP1A2) genetic polymorphism on ROC pharmacokinetics was never described before. The objective of this work was to evaluate the influence of genetic polymorphisms of SLCO1A2 on the pharmacokinetics of rocuronium (ROC). METHODS: Patients undergoing elective surgeries under general anesthesia using rocuronium as a neuromuscular blocker were genotyped for SLCO1A2 polymorphisms in the coding region (41A>G, 382A>T, 404A>T, 502C>T, 516A>C, 559G>A, 830C>A, and 833delA) and in the promoter region (-1105G>A, -1032G>A, -715T>C, -361G>A, and -189_-188insA)...
August 2017: European Journal of Clinical Pharmacology
Chao Zhou, Yang Rong, Teruaki Konishi, Zhaojian Xiang, Fang Zihui, Mei Hong
Organic anion transporting polypeptides (OATPs) are a family of membrane uptake transporters that play important roles in absorption, distribution, metabolism and excretion of a wide range of endogenous and exogenous compounds. OATP members, such as OATP1A2, 1B1 and 1B3, were found to transport numerous anticancer agents. For this reason, these uptake transporters have been proposed to serve as novel and potential therapeutic targets for chemotherapy. Previously published studies from our laboratory demonstrated that OATP1A2 expression was upregulated in breast cancer MCF7 cells after X-ray irradiation and the transport of its substrate methotrexate was increased...
June 2017: Radiation Research
Anton Ivanyuk, Françoise Livio, Jérôme Biollaz, Thierry Buclin
Transporters in proximal renal tubules contribute to the disposition of numerous drugs. Furthermore, the molecular mechanisms of tubular secretion have been progressively elucidated during the past decades. Organic anions tend to be secreted by the transport proteins OAT1, OAT3 and OATP4C1 on the basolateral side of tubular cells, and multidrug resistance protein (MRP) 2, MRP4, OATP1A2 and breast cancer resistance protein (BCRP) on the apical side. Organic cations are secreted by organic cation transporter (OCT) 2 on the basolateral side, and multidrug and toxic compound extrusion (MATE) proteins MATE1, MATE2/2-K, P-glycoprotein, organic cation and carnitine transporter (OCTN) 1 and OCTN2 on the apical side...
August 2017: Clinical Pharmacokinetics
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