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Biopharmaceutics & Drug Disposition

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https://www.readbyqxmd.com/read/29719052/effect-of-single-walled-carbon-nanotubes-on-cytochrome-p450-activity-in-human-liver-microsomes-in-vitro
#1
Yuki Asai, Yukiko Sakakibara, Rina Inoue, Rikako Inoue, Masayuki Nadai, Miki Katoh
Single-walled carbon nanotubes (SWCNTs) are made from a rolled single sheet of graphene with a diameter in the nanometer range. SWCNTs are potential carriers for drug delivery systems because antibodies or drugs can be loaded on their surface; however, their effect on the activities of cytochrome P450 (CYP) remains unclear. The aim of this study was to investigate the effect of two kinds of SWCNTs with different lengths (FH-P- and SO-SWCNTs) on human CYP activity. In addition, other nano-sized carbon materials, such as carbon black, fullerene-C60 , and fullerene-C70 were also evaluated to compare their effects on CYP activities...
May 2, 2018: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/29682747/contribution-of-equilibrative-nucleoside-transporters-1-and-2-to-gemcitabine-uptake-in-pancreatic-cancer-cells
#2
Masato Hioki, Takuya Shimada, Tian Yuan, Takeo Nakanishi, Hidehiro Tajima, Maiko Yamazaki, Rina Yokono, Makiko Takabayashi, Kazuki Sawamoto, Gaku Akashita, Ken-Ichi Miyamoto, Tetsuo Ohta, Ikumi Tamai, Tsutomu Shimada, Yoshimichi Sai
Hepatic arterial infusion (HAI) chemotherapy is expected to be a more effective and safer method to treat the hepatic metastasis of pancreatic cancer than intravenous (i.v.) administration because of higher tumor exposure and lower systemic exposure. To clarify the uptake mechanism of nucleoside anticancer drugs, including gemcitabine (GEM), in pancreatic cancer, we investigated the uptakes of radiolabeled uridine (a general substrate of nucleoside transporters) and GEM in pancreatic cancer cell lines MIA-PaCa2 and As-PC1...
April 22, 2018: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/29679478/randomized-controlled-study-of-bleselumab-askp1240-pharmacokinetics-and-safety-in-patients-with-moderate-to-severe-plaque-psoriasis
#3
Mysore S Anil Kumar, Kim Papp, Ryo Tainaka, Udaya Valluri, Xuegong Wang, Tong Zhu, Christian Schwabe
This study evaluated pharmacokinetics (PK), efficacy, safety, and tolerability of bleselumab - a fully-human anti-CD40 monoclonal recombinant IgG4. Patients with moderate-to-severe psoriasis were randomized on Day 1 to receive bleselumab or placebo on Days 1, 15, and 29 in a dose-escalation of bleselumab 0.1, 0.3, 1.0, or 3.0mg/kg. The safety-analysis set (SAF) and full-analysis set (FAS) included all patients who received bleselumab or placebo, and the PK-analysis set (PKAS) included patients in the SAF with ≥1 quantifiable serum bleselumab concentration...
April 21, 2018: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/29679474/population-pharmacokinetics-of-gliclazide-in-normal-and-diabetic-rabbits
#4
Mastan Shaik, Shabana Shaik, Eswar Kumar Kilari
Gliclazide is a second-generation sulphonylurea drug widely used in the treatment of type 2 diabetes. However, there is no single report to describe the population pharmacokinetics of gliclazide in animal models. This study was aimed to evaluate the population pharmacokinetics (PK) of gliclazide in normal and alloxan-induced diabetic rabbits using nonlinear mixed effects modeling. A total of 90 New Zealand white rabbits were administered with 3 doses (4.13, 8.27 and 16.53 mg/kg b.wt) of gliclazide by an oral route...
April 21, 2018: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/29635775/effects-of-renal-impairment-on-transporter-mediated-renal-reabsorption-of-drugs-and-renal-drug-drug-interactions-a-simulation-based-study
#5
Kristin E Follman, Rutwij A Dave, Marilyn E Morris
Renal impairment (RI) significantly impacts the clearance of drugs through changes in glomerular filtration rate, protein binding and alterations in the expression of renal drug transport proteins and hepatic metabolizing enzymes. The objectives of this study were to quantitatively evaluate the effects of RI on the pharmacokinetics of drugs undergoing renal transporter-mediated reabsorption. We utilized a previously published semi-mechanistic kidney model incorporating physiologically-relevant fluid reabsorption and transporter-mediated active renal reabsorption (PMID: 26341876) in this study...
April 10, 2018: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/29607517/amorphous-solid-dispersions-of-carvedilol-along-with-ph-modifiers-improved-pharmacokinetic-properties-under-hypochlorhydoria
#6
Shimul Halder, Aiko Tabata, Yoshiki Seto, Hideyuki Sato, Satomi Onoue
Carvedilol (CAR) belongs to biopharmaceutics classification system class-II drugs, with poor aqueous solubility and pH-dependent solubility. The present study aimed to develop a novel amorphous solid dispersion (ASD) of CAR with acidic counter ions for pH modifications in microenvironment to improve the pharmacokinetic properties under hypochlorhydric conditions. CAR-ASD was prepared by freeze-drying in combination with counter ions and hydroxypropyl cellulose, and their physicochemical properties including dissolution behavior, storage stability, and photostability were characterized...
April 2, 2018: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/29488238/potencies-of-vitamin-d-analogs-1%C3%AE-hydroxyvitamin-d-3-1%C3%AE-hydroxyvitamin-d-2-and-25-hydroxyvitamin-d-3-in-lowering-cholesterol-in-hypercholesterolemic-mice-in-vivo
#7
Holly P Quach, Tamara Dzekic, Paola Bukuroshi, K Sandy Pang
Vitamin D3 and the synthetic vitamin D analogs, 1α-hydroxyvitamin D3 [1α(OH)D3 ], 1α-hydroxyvitamin D2 [1α(OH)D2 ] and 25-hydroxyvitamin D3 [25(OH)D3 ] were appraised for their vitamin D receptor (VDR) associated-potencies as cholesterol lowering agents in mice in vivo. These precursors are activated in vivo: 1α(OH)D3 and 1α(OH)D2 are transformed by liver CYP2R1 and CYP27A1 to active VDR ligands, 1α,25-dihydroxyvitamin D3 [1,25(OH)2 D3 ] and 1α,25-dihydroxyvitamin D2 [1,25(OH)2 D2 ], respectively. 1α(OH)D2 may also be activated by CYP24A1 to 1α,24-dihydroxyvitamin D2 [1,24(OH)2 D2 ], another active VDR ligand...
April 2018: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/29488228/cytochrome-p450-2c9-natural-antiarthritic-interactions-evaluation-of-inhibition-magnitude-and-prediction-from-in-vitro-data
#8
Boon Hooi Tan, Nafees Ahemad, Yan Pan, Uma Devi Palanisamy, Iekhsan Othman, Beow Chin Yiap, Chin Eng Ong
Many dietary supplements are promoted to patients with osteoarthritis (OA) including the three naturally derived compounds, glucosamine, chondroitin and diacerein. Despite their wide spread use, research on interaction of these antiarthritic compounds with human hepatic cytochrome P450 (CYP) enzymes is limited. This study aimed to examine the modulatory effects of these compounds on CYP2C9, a major CYP isoform, using in vitro biochemical assay and in silico models. Utilizing valsartan hydroxylase assay as probe, all forms of glucosamine and chondroitin exhibited IC50 values beyond 1000 μM, indicating very weak potential in inhibiting CYP2C9...
April 2018: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/29469947/evaluation-of-the-metabolic-capability-of-primary-human-hepatocytes-in-three-dimensional-cultures-on-microstructural-plates
#9
Satoshi Koyama, Hiroshi Arakawa, Manabu Itoh, Norio Masuda, Kentaro Yano, Hajime Kojima, Takuo Ogihara
The NanoCulture Plate (NCP) is a novel microstructural plate designed as a base for the three-dimensional culture of cells/tissues. This study examined whether or not the metabolic capability of human primary hepatocytes is well maintained during culture on NCPs. The hepatocytes formed aggregates after seeding and their ATP content was well maintained during culture for 21 days. Expression of CYP1A2, 2B6, 2C9, 2C19, 2D6, 2E1 and 3A4 mRNAs was detected throughout the 21-day culture period. Addition of CYP substrate drugs (midazolam, diclofenac, lamotrigine and acetaminophen) resulted in the formation of multiple metabolites with a corresponding decrease in the amounts of the unchanged compounds...
April 2018: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/29474740/differences-in-nonclinical-pharmacokinetics-between-species-and-prediction-of-human-pharmacokinetics-of-tak-272-sco-272-a-novel-orally-active-renin-inhibitor
#10
Takuya Ebihara, Mitsuhiro Nishihara, Junzo Takahashi, Fumihiro Jinno, Yoshihiko Tagawa
In the search for orally available drugs, the prediction of human pharmacokinetics (PK) is essential for successfully selecting compounds that will be clinically useful. This report describes the selection of TAK-272 (SCO-272), a novel orally active renin inhibitor, as a clinical candidate via the detailed investigation of nonclinical PK data and human PK prediction. The bioavailability (BA) of TAK-272 after oral administration to rats and monkeys was low, especially in fasted monkeys, and the systemic exposure of TAK-272 was highly variable in monkeys...
March 2018: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/29451686/an-iminium-ion-metabolite-hampers-the-production-of-the-pharmacologically-active-metabolite-of-a-multikinase-inhibitor-kw-2449-in-primates-irreversible-inhibition-of-aldehyde-oxidase-and-covalent-binding-with-endogenous-proteins
#11
Jun Hosogi, Rui Ohashi, Hiroshi Maeda, Kazuhiro Fujita, Junko Ushiki, Takashi Kuwabara, Yorihiro Yamamoto, Toru Imamura
We previously reported that KW-2449, (E)-1-{4-[2-(1H-Indazol-3-yl)vinyl]benzoyl}piperazine, a novel multikinase inhibitor developed for the treatment of leukemia patients, was oxidized to an iminium ion intermediate by monoamine oxidase B (MAO-B) and then converted to its oxo-piperazine form (M1) by aldehyde oxidase (AO). However, it was found that the significant decrease in the pharmacologically active metabolite M1 following repeated administration of KW-2449 in primates might hamper the effectiveness of the drug...
March 2018: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/29451681/verification-of-a-physiologically-based-pharmacokinetic-model-of-ritonavir-to-estimate-drug-drug-interaction-potential-of-cyp3a4-substrates
#12
Ken-Ichi Umehara, Felix Huth, Christina S Won, Tycho Heimbach, Handan He
Ritonavir is one of several ketoconazole alternatives used to evaluate strong CYP3A4 inhibition potential in clinical drug-drug interaction (DDI) studies. In this study, four physiologically based pharmacokinetic (PBPK) models of ritonavir as an in vivo time-dependent inhibitor of CYP3A4 were created and verified for oral doses of 20, 50, 100 and 200 mg using the fraction absorbed (Fa ) and oral clearance (CLoral ) values reported in the literature, because transporter and CYP enzyme reaction phenotyping data were not available...
March 2018: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/29327455/bioactivity-guided-fractionation-of-methanolic-extract-of-terminalia-arjuna-for-its-cyp3a-and-cyp2d-inhibition-in-rat-liver-microsomes
#13
Alice Varghese, Prachi Saboo, Sarika Wairkar
Terminalia arjuna (T. arjuna) is an Indian medicinal plant belonging to the family Combretaceae and possesses numerous therapeutic activities including its immense cardioprotective activity. In the present work, a methanolic bark extract of T. arjuna was evaluated for CYP3A and CYP2D inhibition potential in rat liver microsomes (RLM). Further, the methanolic bark extract was fractionated successively using increasing polarity solvents starting with petroleum ether, chloroform, ethyl acetate and n-butanol. The fractions so obtained were also evaluated for their CYP3A and CYP2D inhibition potential...
March 2018: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/29319909/inhibitory-effects-of-sulfonylureas-and-non-steroidal-anti-inflammatory-drugs-on-in-vitro-metabolism-of-canagliflozin-in-human-liver-microsomes
#14
Sara Algeelani, Dalal Alkhelb, David J Greenblatt
Canagliflozin, used to treat type 2 diabetes mellitus (T2DM), is commonly co-administered with sulfonylureas. The objective of the present study was to evaluate the possible inhibitory effect of sulfonylureas and non-steroidal anti-inflammatory drugs (NSAIDs) on canagliflozin metabolism in vitro. Three sulfonylurea derivatives were evaluated as inhibitors: chlorpropamide, glimepiride and gliclazide. Two other NSAIDs were used as positive control inhibitors: niflumic acid and diclofenac. The rate of formation of canagliflozin metabolites was determined by HPLC analysis of in vitro incubations of canagliflozin as a substrate with and without inhibitors, using human liver microsomes (HLMs)...
March 2018: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/29319897/application-of-a-physiologically-based-pharmacokinetic-model-for-the-prediction-of-bumetanide-plasma-and-brain-concentrations-in-the-neonate
#15
Maria D Donovan, Khaled Abduljalil, John F Cryan, Geraldine B Boylan, Brendan T Griffin
Bumetanide is a loop diuretic that is proposed to possess a beneficial effect on disorders of the central nervous system, including neonatal seizures. Therefore, prediction of unbound bumetanide concentrations in the brain is relevant from a pharmacological prospective. A physiologically-based pharmacokinetic (PBPK) model was developed for the prediction of bumetanide disposition in plasma and brain in adult and paediatric populations. A compound file was built for bumetanide integrating physicochemical data and in vitro data...
March 2018: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/29243851/alterations-in-gene-expression-in-vitamin-d-deficiency-down-regulation-of-liver-cyp7a1-and-renal-oat3-in-mice
#16
Holly P Quach, Keumhan Noh, Stacie Y Hoi, Adrie Bruinsma, Geny M M Groothuis, Albert P Li, Edwin C Y Chow, K Sandy Pang
The vitamin D-deficient model, established in the C57BL/6 mouse after 8 weeks of feeding vitamin D-deficient diets in the absence or presence of added calcium, was found associated with elevated levels of plasma parathyroid hormone (PTH) and plasma and liver cholesterol, and a reduction in cholesterol 7α-hydroxylase (Cyp7a1, rate-limiting enzyme for cholesterol metabolism) and renal Oat3 mRNA/protein expression levels. However, there was no change in plasma calcium and phosphate levels. Appraisal of the liver revealed an up-regulation of mRNA expressions of the small heterodimer partner (Shp) and attenuation of Cyp7a1, which contributed to hypercholesterolemia in vitamin D-deficiency...
February 2018: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/29240983/human-ugt2b7-is-the-major-isoform-responsible-for-the-glucuronidation-of-clopidogrel-carboxylate
#17
Jin-Zi Ji, Bei-Bei Huang, Tong-Tong Gu, Ting Tai, Huan Zhou, Yu-Meng Jia, Qiong-Yu Mi, Meng-Ran Zhang, Hong-Guang Xie
Clopidogrel is predominantly hydrolyzed to clopidogrel carboxylic acid (CCA) by carboxylesterase 1, and subsequently CCA is glucuronidated to clopidogrel acyl glucuronide (CAG) by uridine diphosphate-glucuronosyltransferases (UGTs); however, the UGT isoenzymes glucuronidating CCA remain unidentified to date. In this study, the glucuronidation of CCA was screened with pooled human liver microsomes (HLMs) and 7 human recombinant UGT (rUGT) isoforms. Results indicated that rUGT2B7 exhibited the highest catalytical activity for the CCA glucuronidation as measured with a mean Vmax value of 120...
February 2018: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/29214648/nonlinear-disposition-of-lithium-in-rats-and-saturation-of-its-tubular-reabsorption-by-the-sodium-phosphate-cotransporter-as-a-cause
#18
Yuichi Uwai, Tatsuya Kawasaki, Tomohiro Nabekura
We previously reported the contribution of sodium-phosphate cotransporter to the tubular reabsorption of lithium in rats. In the present study, the dose dependency of the renal handling of lithium was examined in rats. When lithium chloride at 1.25 mg/kg, 2.5 mg/kg and 25 mg/kg was intravenously injected as a bolus, the areas under the plasma concentration-time curve of lithium until 60 minutes were calculated to be 6.23 mEq·min/l, 8.77 mEq·min/l and 64.6 mEq·min/l, respectively. The renal clearance of lithium and its fractional excretion increased with increments in the dose administered...
February 2018: Biopharmaceutics & Drug Disposition
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
#19
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...
February 2018: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/29131354/effect-of-status-epilepticus-on-expression-of-brain-udp-glucuronosyltransferase-1a-in-rats
#20
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...
February 2018: Biopharmaceutics & Drug Disposition
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