| 1. |
- Allmyr, Mats, et al.
(författare)
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Human Exposure to Triclosan via Toothpaste does not change CYP3A4 Activity or Plasma Concentrations of Thyroid Hormones
- 2009
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Ingår i: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7835 .- 1742-7843. ; 105:5, s. 339-344
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Tidskriftsartikel (refereegranskat)abstract
- Triclosan is an antibacterial compound commonly used in cosmetics and personal care products for everyday use. As previously shown, triclosan is found in the plasma, urine and milk from large parts of different human populations. Recent studies have revealed that triclosan is able to activate the human pregnane X receptor in vitro and thus possibly affecting metabolism of drugs in humans via the induction of CYP3A4. Besides, triclosan has been shown to affect thyroid hormonal levels in rats in vivo. In the present study, we investigated if an everyday exposure to triclosan via triclosan-containing toothpaste for 14 days in 12 adult humans caused an increase in plasma 4 beta-hydroxycholesterol, indicative of CYP3A4 induction, and/or alterations in thyroid hormonal status. The plasma triclosan concentrations increased from 0.009-0.81 ng/g to 26-296 ng/g (ranges) upon exposure. Despite this, there were no significant changes in plasma levels of either plasma 4 beta-hydroxycholesterol or thyroid hormones during the exposure. This indicates that the normal use of triclosan-containing toothpaste is not likely to alter metabolism of drugs via CYP3A4 induction or cause adverse events because of thyroid disturbances in humans.
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| 2. |
- Bay, Bjorn, et al.
(författare)
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Response of human oral mucosa and skin to histamine provocation : laser Doppler perfusion imaging discloses differences in the nociceptive nervous system
- 2009
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Ingår i: Acta Odontologica Scandinavica. - London : Taylor & Francis. - 0001-6357 .- 1502-3850. ; 67:2, s. 99-105
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To investigate the existence of histamine-excitable nerve fibers in the oral mucosa and to compare the response to histamine provocation in healthy volunteers with that in a small group of patients with chronic oral pain. Material and methods. Thirteen healthy volunteers and six patients suffering from chronic oral pain took part in the study. Blood perfusion was monitored in the hard palate, the tongue, and the skin of the cheek using laser Doppler perfusion imaging (Perimed; Sweden). Baseline scannings were performed, followed by 15 scannings after iontophoresis of histamine (1%). A free description of the sensations was then obtained from the participants after finishing the measurements. Results. Compared to pre-histamine scanning, histamine application resulted in a considerable increase in blood perfusion in all regions (p0.001) that was significantly higher in skin than in oral mucosa (p0.001). There were no significant differences between the healthy volunteers and the patients regarding baseline blood flow, increased blood perfusion, or flare size after histamine provocation. The sensory impression was reported to be more persistent and intense in the skin than in the oral mucosa. No effect on mucosa could be detected by visual inspection. Conclusions. Intra-oral flare could be induced by activating histamine-excitable nerve fibers. Both duration and intensity of the flare were considerably less pronounced than in the control skin site. Histamine application was not clearly associated with itch.
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| 3. |
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| 4. |
- Englund, Gunilla, et al.
(författare)
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Efflux transporters in ulcerative colitis : decreased expression of BCRP (ABCG2) and Pgp (ABCB1)
- 2007
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Ingår i: Inflammatory Bowel Diseases. - : Oxford University Press (OUP). - 1078-0998 .- 1536-4844. ; 13:3, s. 291-297
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Tidskriftsartikel (refereegranskat)abstract
- Background: Efflux transport proteins are important components of the intestinal barrier against bacterial toxins, carcinogens, and drugs. This investigation was conducted to determine the expression of Breast Cancer Resistance Protein (BCRP/ABCG2), P-glycoprotein (Pgp/MDR1/ABCB1), and Multidrug Resistance Protein 2 (MRP2/ABCC2) in the gut mucosa of patients with ulcerative colitis (UC). Methods: Patients were thoroughly diagnosed according to well-established clinical, endoscopic, and histologic criteria to be included in the group of patients with active UC (n = 16) or UC in remission (n = 17). Colonic and rectal mucosa from patients with UC were compared with tissues from control subjects (n = 15). The mRNA expression (TaqMan) of the efflux transporters and the proinflammatory cytokines interleukin (IL)-1β and IL-6 was determined. Western blot was used in the analysis of protein expression and the tissue localization of BCRP was determined with confocal microscopy. Results: BCRP and Pgp expression was strongly reduced in individuals with active inflammation compared with controls and was negatively correlated with the levels of IL-6 mRNA. The BCRP staining of colonic epithelium seen in healthy mucosa was diminished in inflamed tissues, with concurrent disruption of epithelial F-actin structure. Conclusions: Two of the efflux transporters of importance for the barrier function of the gut mucosa, Pgp and BCRP, are expressed at strongly reduced levels during active inflammation in patients with UC. Investigations are warranted to determine whether the low levels of efflux transporters during active UC contribute to altered transport and tissue exposure of carcinogens, bacterial toxins, and drugs.
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| 5. |
- Englund, Gunilla, 1975-
(författare)
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Interindividual Variability of Drug Transport Proteins : Focus on Intestinal Pgp (ABCB1) and BCRP (ABCG2)
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The appearance of adverse drug reactions is a common reason for hospitalization in Western countries. Research on underlying biological mechanisms for interindividual variability in drug response aims to better identify patients with exceptional genetic traits, disease conditions or risk of drug-drug interactions and thereby help to prevent adverse drug reactions. Active transport mechanisms are involved in the absorption and disposition of several therapeutic agents. The main objective of this thesis was to investigate factors potentially affecting transport proteins and thus contributing to variability in drug absorption and disposition. Studies of physiological, genetic, environmental, and pathological factors were included. The main focus was the two ATP-binding cassette (ABC) transporters: P-glycoprotein 170 (Pgp) and Breast Cancer Resistance Protein (BCRP). Quantification of transport protein mRNAs along the human intestine indicated that eight of the nine investigated drug transporters were expressed in a region-dependent manner. Effects of drug-drug interactions may therefore vary depending on the site of absorption. The genetic aspect was illustrated by identification of sequence variation in the gene encoding BCRP, the most highly expressed ABC transporter along the human intestine. Drug-drug interactions are important environmental causes of interindividual variability. An evaluation of the effects of Pgp-mediated drug-drug interactions showed that patients receiving Pgp inhibitors had elevated serum concentrations of the Pgp substrate digoxin and that digoxin concentrations were positively correlated with the number of co-administered Pgp inhibitors. The final topic in this thesis was that of drug-disease interactions. BCRP and Pgp were down-regulated during active inflammation in patients with ulcerative colitis. This may contribute to altered concentrations of drug in the intestinal mucosa during periods of inflammation and possibly to changes in drug absorption. To summarize, results of this thesis emphasize the complex background to the interindividual variability of drug transport proteins, where physiological, genetic, environmental and pathological factors all can contribute.
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| 6. |
- Englund, Gunilla, et al.
(författare)
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Regional levels of drug transporters along the human intestinal tract : Co-expression of ABC and SLC transporters and comparison with Caco-2 cells
- 2006
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Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 29:3-4, s. 269-277
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Tidskriftsartikel (refereegranskat)abstract
- A vast number of drugs are subjected to active or facilitated transport and multiple transport mechanism may contribute to the net flux during drug absorption. The main objective of this study was to quantify the regional mRNA expression and determine the co-expression of drug transporters from the ABC (Pgp, BCRP, MRP2, MRP3) and SLC (PEPT1, MCT1, OATPB, OCTN2, OCT1) families along the human intestine (duodenum, jejunum, ileum, and colon). A second objective was to compare the transporter expression between the different intestinal regions and Caco-2 cells. Eight out of nine of the investigated transporters exhibited significant regional differences in expression. OATPB was the only transporter that did not show a region-dependency in the expression along the human intestinal canal. The expression of Pgp, BCRP, OCTN2 and MCT1 differed along the small intestine, but the expression differences were greater than five-fold only for Pgp. The rank order of transcript prevalence was identical in the ileum and the jejunum. Between the ileum and colon, seven transcripts were differentially expressed, and MCT1, OCTN2 and MRP3 were expressed at higher levels in the colon than in the small intestine. The expression of transporters in Caco-2 was closest to the expression pattern in the small intestine, although the expression of OATPB, BCRP and MRP2 differed more than five-fold between the Caco-2 cells and ileum. In conclusion, this study provides quantitative data on the expression of transporters from the ABC and SLC families along the human intestine, which can be useful in the interpretation of clinical studies where more than one intestinal transporter contribute to the net transport and in the computer modelling of drug absorption.
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| 7. |
- Matsson, Pär, et al.
(författare)
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A Global Drug Inhibition Pattern for the Human ATP-Binding Cassette Transporter Breast Cancer Resistance Protein (ABCG2)
- 2007
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Ingår i: Journal of Pharmacology and Experimental Therapeutics. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0022-3565 .- 1521-0103. ; 323:1, s. 19-30
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Tidskriftsartikel (refereegranskat)abstract
- In this article, we explore the entire structural space of registered drugs to obtain a global model for the inhibition of the drug efflux transporter breast cancer resistance protein (BCRP; ABCG2). For this purpose, the inhibitory effect of 123 structurally diverse drugs and drug-like compounds on mitoxantrone efflux was studied in Saos-2 cells transfected with human wild-type (Arg482) BCRP. The search for BCRP inhibitors throughout the drug-like chemical space resulted in the identification of 29 previously unknown inhibitors. The frequency of BCRP inhibition was 3 times higher for compounds reported to interact with other ATP-binding cassette (ABC) transporters than for compounds without reported ABC transporter affinity. An easily interpreted computational model capable of discriminating inhibitors from noninhibitors using only two molecular descriptors, octanol-water partition coefficient at pH 7.4 and molecular polarizability, was constructed. The discriminating power of this two-descriptor model was 93% for the training set and 79% for the test set, respectively. The results were supported by a global pharmacophore model and are in agreement with a two-step mechanism for the inhibition of BCRP, where both the drug's capacity to insert into the cell membrane and to interact with the inhibitory binding site of the transporter are important.
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