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Biopharmaceutics & Drug Disposition

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https://www.readbyqxmd.com/read/29136681/assessment-of-multiple-cytochrome-p450-activities-in-metabolically-inactivated-human-liver-microsomes-and-roles-of-p450-2c-isoforms-in-reaction-phenotyping-studies
#1
Norie Murayama, Kanako Yajima, Mikiko Hikawa, Kanami Shimura, Yu Ishii, Masaki Takada, Yasuhiro Uno, Masahiro Utoh, Kazuhide Iwasaki, Hiroshi Yamazaki
The fraction of substrate metabolized (fm ) can be used to estimate drug interactions and can be determined by comparison of the intrinsic clearances (CLint ) of victim drugs obtained from inhibited and uninhibited hepatic enzymes. Commercially available human liver microsomes were recently developed in which one cytochrome P450 (P450) isoform is selectively inactivated. These inactivated liver microsomes were used to evaluate the roles of P450 2C isoforms in the depletion and oxidation of probe substrates...
November 14, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/29131354/effect-of-status-epilepticus-on-expression-of-brain-udp-glucuronosyltransferase-1a-in-rats
#2
Yuki Asai, Hatsuna Tanaka, Masayuki Nadai, Miki Katoh
Status epilepticus (SE) involves severe epileptic seizures that cause oxidative stress in the brain. Oxidative stress is known to influence uridine 5'-diposphate-glucuronosyltransferase (UGT) 1A expression. The present study aimed at elucidating the effect of SE on Ugt1a1, Ugt1a6, and Ugt1a7 expression in the rat brain. Kainic acid was used to create an animal model of SE. Sprague-Dawley rats were treated intraperitoneally with 10 mg/kg kainic acid. Ugt1a1 and Ugt1a7 mRNA levels were increased by SE in the cortex and hippocampus (Ugt1a1: 4...
November 13, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/29127714/a-rule-of-unity-for-human-intestinal-absorption-3-application-to-pharmaceuticals
#3
Raj B Patel, Samuel H Yalkowsky
The rule of unity is based on a simple absorption parameter, Π, that can accurately predict whether or not an orally administered drug will be well absorbed or poorly absorbed. The intrinsic aqueous solubility and octanol-water partition coefficient, along with the drug dose are used to calculate Π. We show that a single delineator value for Π exist that can distinguish whether a drug is likely to be well absorbed (FA ≥ 0.5) or poorly absorbed (FA < 0.5) at any specified dose. The model is shown to give 82...
November 11, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/29065218/renal-vectorial-transport-of-berberine-mediated-by-organic-cation-transporter-2-oct2-and-multidrug-and-toxin-extrusion-proteins-1-mate1-in-rats
#4
Rong Shi, Yuanyuan Yang, Zhangyao Xu, Yan Dai, Zheng Min, Tianming Wang, Yuanyuan Li, Yueming Ma
Berberine, a well-known plant alkaloid derived from Rhizoma coptidis, has potential applications as a therapeutic drug for diabetic nephropathy. However, the transporter-mediated renal transport of berberine remains largely unclear. This study aimed to investigate the renal transport mechanism of berberine using transfected cells, kidney slices, and animal experiments. In Madin-Darby canine kidney (MDCK) cells stably expressing rat OCT2 (MDCK-rOCT2) and kidney slices, saturable and non-saturable uptake of berberine was observed, and corticosterone could inhibit the uptake of berberine, with IC50 values of 0...
October 24, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/29059459/molecular-cloning-and-tissue-distribution-of-a-novel-marmoset-abc-transporter
#5
Shotaro Uehara, Yasuhiro Uno, Takashi Inoue, Erika Sasaki, Hiroshi Yamazaki
Common marmosets (Callithrix jacchus) have been recognized as a useful small non-human primate model in preclinical testing for drug development. In this study, a cDNA of novel ATP-dependent efflux transporter ABCB1 was cloned from marmoset liver tissue. Marmoset ABCB1 cDNA encodes a protein of 1,279 amino acid residues (MW = 141.4 kDa) containing characteristic regions of an ATP-binding cassette (ABC) protein, two hydrophobic transmembrane regions, and two cytoplasmic nucleotide-binding regions, similar to human ABCB1...
October 23, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/29055041/the-possible-clinical-impact-of-risperidone-on-p-glycoprotein-mediated-transport-of-tacrolimus-a-case-report-and-in-vitro-study
#6
Nao Watanabe, Hiroki Higashi, Saki Nakamura, Keiko Nomura, Yuichi Adachi, Masato Taguchi
The authors encountered the case of an 8-fold increase in the concentration/dose (C/D) ratio of tacrolimus (TAC) following the coadministration of voriconazole (VRCZ) in a hematopoietic stem cell transplantation (HSCT) recipient. The interaction observed was much greater than expected and the patient had also been treated with oral risperidone (RSP). We hypothesized that cytochrome P450 (CYP)3A inhibition of the small intestine by VRCZ and P-glycoprotein (P-gp) inhibition of the small intestine by RSP exerted a synergistic effect on the bioavailability of TAC...
October 20, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/29055025/contribution-of-equilibrative-nucleoside-transporter-s-to-intestinal-basolateral-and-apical-transports-of-anticancer-trifluridine
#7
Koichi Takahashi, Kunihiro Yoshisue, Masato Chiba, Takeo Nakanishi, Ikumi Tamai
Trifluridine (FTD) exhibits anticancer activities after its oral administration despite its hydrophilic nature. We previously reported that concentrative nucleoside transporter (CNT) 1 mediates the apical uptake of FTD in human small intestinal epithelial cells (HIECs). In the present study, FTD was also identified as a substrate for equilibrative nucleoside transporter (ENT) 1 and ENT2 in transporter gene-transfected cells. An immunocytochemical analysis revealed that ENT1 was expressed at the basolateral and apical membranes of HIECs...
October 20, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28972677/hepatocellular-uptake-of-cyclodextrin-complexed-curcumin-during-liver-preservation-a-feasibility-study
#8
Saber Abdelkader Saidi, Nicolas Meurisse, Ina Jochmans, Veerle Heedfeld, Tine Wylin, Jaakko Parkkinen, Jacques Pirenne, Diethard Monbaliu, Abdelfattah El Feki, Jos van Pelt
Increasing demand for donor organs and decreasing organ quality is prompting research toward new methods to reduce ischemia reperfusion injury (IRI). Several strategies have been proposed to protect the preserved organ from this injury. Before curcumin/dextrin complex (CDC), a potent antioxidant and anti-inflammatory agent, can be used clinically we need to better understand the intracellular uptake under hypothermic conditions on rat model of liver donation after circulatory death (DCD) and brain death (DBD)...
October 3, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28960401/prediction-of-drug-drug-interactions-using-physiologically-based-pharmacokinetic-models-of-cyp450-modulators-included-in-simcyp-software
#9
Niloufar Marsousi, Jules A Desmeules, Serge Rudaz, Youssef Daali
In recent years, Physiologically-Based PharmacoKinetic (PBPK) modeling has received growing interest as a useful tool for assessment of drug PK. It has demonstrated to be informative and helpful to quantify the modification in drug exposure due to specific physio-pathological conditions, age, genetic polymorphisms, ethnicity and particularly drug-drug interactions (DDIs). In this paper, the prediction success of DDIs involving various cytochrome P450 isoenzyme (CYP) modulators namely ketoconazole (a competitive inhibitor of CYP3A), itraconazole (a competitive inhibitor of CYP3A), clarithromycin (a mechanism-based inhibitor of CYP3A), quinidine (a competitive inhibitor of CYP2D6), paroxetine (a mechanism-based inhibitor of CYP2D6), ciprofloxacin (a competitive inhibitor of CYP1A2), fluconazole (a competitive inhibitor of CYP2C9/2C19) and rifampicin (an inducer of CYP3A) were assessed using Simcyp® software...
September 28, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28948605/influence-of-body-composition-on-disposition-of-the-highly-fat-distributed-compound-as-analyzed-by-physiologically-based-pharmacokinetic-pbpk-modeling-and-simulation
#10
Akihiko Goto, Yoshihiko Tagawa, Yuu Moriya, Sho Sato, Masami Yamamoto, Takeshi Wakabayashi, Tetsuya Tsukamoto, Joost DeJongh, Tamara J van Steeg, Toshiya Moriwaki, Satoru Asahi
A recent study suggested that the pharmacokinetics (PK) of highly-fat distributed compounds can be affected by acute changes in the volume of adipose tissue. The present study investigates possible influences of body composition on the disposition of the highly lipophilic compound TAK-357 in two rat strains. Physiologically-based PK (PBPK) modeling and simulation was applied on single and multiple dose PK data of TAK-357 in obese Wistar fatty rats and Wistar lean rats having approximately 45% and 13% body fat, respectively...
September 25, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28946176/species-related-exposure-of-phase-ii-metabolite-gemfibrozil-1-o-%C3%AE-glucuronide-between-human-and-mice-a-net-induction-of-mouse-p450-activity-was-revealed
#11
Min Luo, Manyun Dai, Hante Lin, Minzhu Xie, Jiao Lin, Aiming Liu, Julin Yang
Gemfibrozil is a fibrate drug widely used for dyslipidemia associated with atherosclerosis. Clinically, both gemfibrozil and its phase II metabolite gemfibrozil1-O-β-glucuronide (gem-glu) are involved in drug-drug interaction (DDI). But the DDI risk caused by gem-glu between human and mice has not been compared. In this study, 6 volunteers were recruited and took therapeutic dose of gemfibrozil for 3 days for examination of the gemfibrozil and gem-glu level in human. Male mice were fed a gemfibrozil diet (0...
September 25, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28926871/multiple-organic-cation-transporters-contribute-to-the-renal-transport-of-sulpiride
#12
Liping Li, Yayun Weng, Wei Wang, Mengru Bai, Hongmei Lei, Hui Zhou, Huidi Jiang
Sulpiride, a selective dopamine D2 receptor blocker, is widely used for treatment of schizophrenia, depression, and gastric/duodenal ulcers. Because of the great majority of sulpiride in positive charged at physiological pH7.4, and ~70% of dose recovered in urine in unchanged form after human intravenous administration of sulpiride, we believe transporters play an important role in renal excretion of sulpiride. The aim of the present study was to explore which transporters contribute to the renal disposition of sulpiride...
September 19, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28866862/acetylshikonin-is-a-novel-non-selective-cytochrome-p450-inhibitor
#13
Jong Cheol Shon, Nguyen Minh Phuc, Won Cheol Kim, Jae Kyung Heo, Zhexue Wu, Hyunyoung Lee, Kwang-Hyeon Liu
Acetylshikonin is biologically active compound with anti-cancer and anti-inflammatory activity, which is isolated from the root of Lithospermum erythrorhizoma. We have recently discovered a inhibitory effect of acetylshikonin against CYP2J2 activity. Based on this result, we expanded our study to evaluate the inhibitory effects of acetylshikonin against nine different cytochrome P450 (P450) isoforms in human liver microsomes (HLMs) using substrate cocktails incubation assay. Acetylshikonin showed strong inhibitory effect against all P450s tested with IC50 values of 1...
September 3, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28865089/impact-of-enzalutamide-and-its-main-metabolite-n-desmethyl-enzalutamide-on-pharmacokinetically-important-drug-metabolizing-enzymes-and-drug-transporters
#14
Johanna Weiss, Jutta Kocher, Corina Mueller, Stephanie Rosenzweig, Dirk Theile
Enzalutamide is a new drug against castration-resistant prostate cancer. Recent data indicate profound induction of drug metabolizing enzymes (e.g. cytochrome P450 isoenzyme (CYP) 3A4) but comprehensive in vitro data on other CYP enzymes, drug conjugating enzymes or drug transporters is scarce. Moreover, mechanisms of induction are poorly investigated and the effects of the active metabolite N-desmethyl enzalutamide are unknown. Using LS180 cells as an induction model and quantitative real-time reverse transcription polymerase chain reaction, our study demonstrated a concentration-dependent induction of CYP1A1, CYP1A2, CYP3A5, CYP3A4, UGT1A3, UGT1A9, ABCB1, ABCC2, and ABCG2 mRNA...
September 1, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28849584/5-fluorouracil-treatment-alters-the-expression-of-intestinal-transporters-in-rats
#15
Keiichi Yotsumoto, Takeshi Akiyoshi, Naoki Wada, Ayuko Imaoka, Hisakazu Ohtani
5-Fluorouracil (5-FU), an anticancer drug, causes severe gastrointestinal damage, which may affect the absorption of orally administered drugs including the substrates of intestinal uptake and efflux transporters. In this study, we aimed to quantitatively investigate the effect of 5-FU-induced intestinal damage on the expression of intestinal transporters; P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and peptide transporter 1 (PEPT1) in rats. The rats were treated with 5-FU (30 mg/kg/day, p...
August 28, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28608480/sgk1-nedd4-2-signaling-pathway-regulates-the-activity-of-human-organic-anion-transporters-3
#16
Haoxun Wang, Guofeng You
Human organic anion transporter 3 (hOAT3) is localized at the basolateral membrane of renal proximal tubule cells and facilitates the renal secretion of numerous clinical drugs, including anti-HIV therapeutics, anti-tumor drugs, antibiotics, antihypertension drugs and anti-inflammatories. The present study explored the role of serum and glucocorticoid-inducible kinase 1 (sgk1) in the regulation of hOAT3. It was shown that over-expression of sgk1 in hOAT3-expressing cells stimulated hOAT3 transport activity by enhancing the transporter expression at the plasma membrane, kinetically reflected as an increased maximal transport velocity Vmax without substantial change in the substrate-binding affinity Km ...
November 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28801980/effects-of-proton-pump-inhibitors-and-famotidine-on-elimination-of-plasma-methotrexate-evaluation-of-drug-drug-interactions-mediated-by-organic-anion-transporter-3
#17
Katsuya Narumi, Yu Sato, Masaki Kobayashi, Ayako Furugen, Kumiko Kasashi, Takehiro Yamada, Takanori Teshima, Ken Iseki
Methotrexate (MTX) is an antifolate agent used in the treatment of numerous types of cancer, and eliminated by active tubular secretion via organic anion transporter 3 (OAT3). Gastric antisecretory drugs, such as proton pump inhibitors (PPIs) and histamine H2 receptor antagonists, are widely used among patients with cancer in clinical practice. The aim of the present study was to analyze the potential drug-drug interactions between MTX and gastric antisecretory drugs in high-dose MTX (HD-MTX) therapy. We retrospectively analyzed the impact of PPIs on the plasma MTX concentration on 73 cycles of HD-MTX therapy performed in 43 patients...
August 12, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28758225/metabolism-of-7-ethoxycoumarin-flavanone-and-steroids-by-cytochrome-p450-2c9-variants
#18
Tomohide Uno, Ryosuke Nakano, Kengo Kanamaru, Shinji Takenaka, Yuichi Uno, Hiromasa Imaishi
CYP2C9 is a human microsomal cytochrome P450c (CYP). Much of the variation in CYP2C9 levels and activity can be attributed to polymorphisms of this gene. Wild-type CYP2C9 and mutants were coexpressed with NADPH-cytochrome P450 reductase in Escherichia coli. The hydroxylase activities toward 7-ethoxycoumarin, flavanone and steroids were examined. Six CYP2C9 variants showed Soret peaks (450 nm) typical of P450 in reduced CO-difference spectra. CYP2C9.38 had the highest 7-ethoxycoumarin de-ethylase activity. All the CYP2C9 variants showed lower flavanone 6-hydroxylation activities than CYP2C9...
July 30, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28744858/d-malate-decreases-renal-content-of-%C3%AE-ketoglutarate-a-driving-force-of-organic-anion-transporters-oat1-and-oat3-resulting-in-inhibited-tubular-secretion-of-phenolsulfonphthalein-in-rats
#19
Yuichi Uwai, Tatsuya Kawasaki, Tomohiro Nabekura
d-Malate inhibits a Krebs cycle enzyme and the tubular transport of α-ketoglutarate, an intermediate of the Krebs cycle and the driving force for rat organic anion transporter 1 (rOAT1) and rOAT3 in the kidney. This study examined the effects of d-malate on the rat organic anion transport system. The uptake of 6-carboxyfluorescein by HEK293 cells expressing rOAT1 or rOAT3 was not affected by d-malate and l-malate. Up to 60 min after the intravenous injection of phenolsulfonphthalein (PSP), a typical substrate of the renal organic anion transporters, as a bolus to rats, 47...
July 25, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28741675/pharmacokinetics-of-dinalbuphine-sebacate-and-nalbuphine-in-human-after-intramuscular-injection-of-dinalbuphine-sebacate-in-an-extended-release-formulation
#20
Yu En Tien, Wen-Chuan Huang, Hui-Yuan Kuo, Lily Tai, Yow-Shieng Uang, Wendy H Chern, Jin-Ding Huang
Nalbuphine is a semi-synthetic opioid indicated for the relief of moderate to severe pain. Its short half-life requires frequent injections in clinical practice, resulting in a greater incidence of adverse events. A prodrug of nalbuphine has been developed, dinalbuphine sebacate (DNS), dissolved in a simple oil-based injectable formulation, which could deliver and maintain an effective blood level of nalbuphine. An open-label, prospective, two-period study was performed in healthy volunteers to verify the extended blood concentration profile of nalbuphine...
July 25, 2017: Biopharmaceutics & Drug Disposition
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