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Biopharmaceutics & Drug Disposition

Kentaro Konishi, Tsuyoshi Minematsu, Yasuhisa Nagasaka, Kenji Tabata
We previously verified a physiologically-based pharmacokinetic (PBPK) model for mirabegron in healthy subjects using the Simcyp Simulator by incorporating data on the inhibitory effect on cytochrome P450 (CYP) 2D6 and multi-elimination pathway mediated by CYP3A4, uridine 5'-diphosphate-glucuronosyltransferase (UGT) 2B7, and butyrylcholinesterase (BChE). The aim of this study was to use this PBPK model to assess the magnitude of drug-drug interactions (DDIs) in an elderly population with severe renal impairment (sRI), which has not been evaluated in clinical trials...
April 15, 2019: Biopharmaceutics & Drug Disposition
Han Xing, Chang Ren, Ying Kong, Chen Ning, Dexuan Kong, Yongjie Zhang, Di Zhao, Ning Li, Zeyu Wang, Xijing Chen, Yang Lu
GL-V9, a derivative of wogonin, has potent anti-cancer activity. The absorption and metabolism of this compound have not been systematically investigated. This study aims to illustrate the pharmacokinetic characters of GL-V9 by exploring its metabolic status under different administration routes. To further clarify the absorption mechanism of GL-V9, in situ single-pass perfusion model and Caco-2 cell monolayer model were applied. Meanwhile, microsomal incubation system was employed to evaluate enzyme kinetic parameters...
March 31, 2019: Biopharmaceutics & Drug Disposition
Masahiro Yahata, Yuji Ishii, Tetsuya Nakagawa, Takao Watanabe, Kiyoko Bando
The metabolism and pharmacokinetics of DSP-0565 [2-(2'-fluoro[1,1'-biphenyl]-2-yl)acetamide], an antiepileptic drug candidate, was investigated in rats, dogs, and humans. In human hepatocytes, [14 C]DSP-0565 was primarily metabolized via amide bond hydrolysis to (2'-fluoro[1,1'-biphenyl]-2-yl)acetic acid (M8), while in rat and dog hepatocytes, it was primarily metabolized via both hydrolysis to M8 and hydroxylation at the benzene ring or the benzyl site to oxidized metabolites. After single oral administration of [14 C]DSP-0565 to rats and dogs, the major radioactivity fraction was recovered in the urine (71-72% of dose) with a much smaller fraction recovered in feces (23-25% of dose)...
March 28, 2019: Biopharmaceutics & Drug Disposition
Yun Kim, Oliver Hatley, Su-Jin Rhee, SoJeong Yi, Hyun A Lee, Sumin Yoon, Jae-Yong Chung, Kyung-Sang Yu, Howard Lee
Physiologically based pharmacokinetic (PBPK) modeling and simulation is a useful tool in predicting the PK profiles of a drug, assessing the effects of covariates such as demographics, ethnicity, genetic polymorphisms, and disease status on the PK, and evaluating the potential of drug-drug interactions. We developed a Korean-specific virtual population for the SimCYP® Simulator (version 15 used) and evaluated the population's predictive performance using six substrate drugs (midazolam, S-warfarin, metoprolol, omeprazole, lorazepam, and rosuvastatin) of five major DMEs and two transporters...
March 28, 2019: Biopharmaceutics & Drug Disposition
Asma Radwan, Rand Jayyousi, Nasr Shraim, Abdel Naser
No abstract text is available yet for this article.
March 19, 2019: Biopharmaceutics & Drug Disposition
Chengcheng Zhao, Zheming Ying, Dong Hao, Wenjie Zhang, Xixiang Ying, Guanlin Yang
Olerciamide A (OA), as a new alkaloid isolated from Portulaca oleracea L., has been proved to possess a low bioavailability (F) after oral administration in rats in our previous study. Hence, to clarify the reasons of its low bioavailability, the hepatic, gastric and intestinal first-pass effect models were established, and a rapid, sensitive UHPLC method were validated and applied for the determination after dosed via femoral, portal, gastric and intestinal routes.. Being the inhibitors of CYP3A and P-gp, verapamil, midazolam and borneol at low and high dose groups were selected to improve the low bioavailability of OA...
February 10, 2019: Biopharmaceutics & Drug Disposition
Hyun-Ji Kim, Hyunyoung Lee, Hyeon-Kyeong Ji, Taeho Lee, Kwang-Hyeon Liu
Testing for the potential drug interactions of new chemical entities is essential when developing a novel drug. In this study, we designed an assay to evaluate drug interactions with 10 major human cytochrome P450 (P450) enzymes incubated in liver microsomes, involving 12 probe substrates with two cocktail incubation sets used in a single liquid chromatography-tandem mass spectrometry (LC-MS/MS) run. The P450 substrate composition in each cocktail set was optimized to minimize solvent effects and mutual drug interactions among substrates as follows: cocktail A was composed of phenacetin for CYP1A2, bupropion for CYP2B6, amodiaquine for CYP2C8, diclofenac for CYP2C9, S-mephenytoin for CYP2C19, and dextromethorphan for CYP2D6; cocktail B was composed of coumarin for CYP2A6, chlorzoxazone for CYP2E1, astemizole for CYP2J2, and midazolam, nifedipine, and testosterone for CYP3A...
February 7, 2019: Biopharmaceutics & Drug Disposition
Harunobu Tahara, Miwa Watanabe, Maki Hasegawa
CYP3A probe drugs such as midazolam and endogenous markers, and plasma 4β-hydroxycholesterol (4β-OHC) and urinary 6β-hydroxycortisol-to-cortisol ratios (6β-OHC/C) have been used as markers of CYP3A induction in cynomolgus monkeys, as with humans. However, there is limited information on their sensitivity and ability to detect CYP3A induction, as most studies were evaluated only at a high dose of the inducer, rifampicin (RIF; 20 mg/kg). In the present study, the CYP3A induction by RIF over a range doses of 0...
February 6, 2019: Biopharmaceutics & Drug Disposition
Jiehong Kong, Yajing Qiu, Yuan Li, Hongjian Zhang, Weipeng Wang
Multidrug resistance (MDR) is common in patients and has been linked to transforming growth factor-β1 (TGF-β1) and overexpression of drug efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), although molecular mechanisms remain largely unknown. Here, we aimed to investigate the mechanisms underlying TGF-β1-induced MDR in hepatocellular carcinoma (HCC) cells. We found that TGF-β1 upregulated HOX transcript antisense RNA (HOTAIR) expression in HCC cells. When drosophila mothers against decapentaplegic 4 (SMAD4) was silenced, HOTAIR expression was accordingly reduced...
January 30, 2019: Biopharmaceutics & Drug Disposition
Tsuyoshi Takahashi, Yasuhiro Uno, Hiroshi Yamazaki, Toshiyuki Kume
Hepatic uptake of clinical drugs mediated by human hepatic organic anion transporting polypeptides (OATP/SLCO) has been extensively reported. In this study, hepatic uptake by recombinantly expressed monkey OATP1B1, OATP1B3, and OATP2B1 was investigated using three human OATP1B1 and OATP1B3 substrates (pitavastatin, pravastatin, and rosuvastatin) and one OATP1B3 substrate (telmisartan), of which governmental drug interaction guidelines recommend, and 7 reported clinical drugs. Uptake of known human probes into recombinant OATP-expressing cells was significantly greater than that of mock cells...
January 16, 2019: Biopharmaceutics & Drug Disposition
Pil Joung Cho, Ju-Hyun Kim, Hye Suk Lee, Jeong Ah Kim, Sangkyu Lee
Licoricidin is a major prenylated isoflavone of Glycyrrhiza uralensis Fisch. (Leguminosae), and its pharmacological effects have been reported frequently. Typically, flavonoids having multiple hydroxyl groups are unambiguous substrates for glucuronyl conjugation by UDP-glucuronosyltransferases (UGTs). The pharmacological effects of flavonoids are derived from the conjugation of glucuronide to yield the bioactive metabolite. Here, we investigated the metabolism of licoricidin in pooled human liver microsomes (HLMs) using high-resolution quadrupole-orbitrap mass spectrometry...
January 12, 2019: Biopharmaceutics & Drug Disposition
Biljana Gatarić, Jelena Parojčić
Solubility and permeability are recognized as key parameters governing drug intestinal absorption and represent the basis for biopharmaceutics drug classification. The Biopharmaceutics Classification System (BCS) is widely accepted and adopted by regulatory agencies. However, currently established low/high permeability and solubility boundaries are subject of the ongoing scientific discussion. The aim of the present study is to apply data mining analysis on the selected drugs data set in order to develop human permeability predictive model based on selected molecular descriptors, and perform data clustering and classification to identify drug subclasses with respect to dose/solubility ratio (D/S) and effective permeability (Peff )...
January 11, 2019: Biopharmaceutics & Drug Disposition
Shinji Kobuchi, Mako Akutagawa, Yukako Ito, Toshiyuki Sakaeda
Capecitabine is a 5-fluorouracil (5-FU) derivative that is used widely in the treatment of colorectal cancer. The plasma ratio of dihydrouracil (UH2 ) to uracil (Ura) is expected to gain relevance as an indirect-response biomarker to estimate the activity of dihydropyrimidine dehydrogenase (DPD). The latter is a rate-limiting enzyme in the catabolism of 5-FU in the capecitabine-based regimen. However, the relationship between the pharmacokinetics of capecitabine and the plasma UH2 /Ura ratio is still unknown...
December 28, 2018: Biopharmaceutics & Drug Disposition
Ikumi Washio, Takeo Nakanishi, Naoki Ishiguro, Bojan Bister, Ikumi Tamai
P-glycoprotein (P-gp, multidrug resistance 1 (MDR1)) overexpression confers multidrug resistance to cancer cells, and P-gp in cell lines transfected with MDR1 or selected with chemotherapeutics significantly affect the anticancer drug efficacy. Although human cancer cell line panels consisting of defined tumor cell lines expressing endogenous P-gp have been used to screen drugs in pharmaceutical industries, endogenous P-gp affecting in vitro anticancer drug efficacy is unclear. We assessed the impact of P-gp expression on anticancer drug efficacy by using five colon cancer cell lines expressing varying endogenous P-gp levels and by selecting from the Cancer Cell Line Encyclopedia (CCLE)...
December 16, 2018: Biopharmaceutics & Drug Disposition
Neha Maharao, Jurgen Venitz, Phillip M Gerk
The present study evaluated the potential of five generally recognized as safe (GRAS) or dietary compounds (α-mangostin, chrysin, ginger extract, pterostilbene and silybin) to inhibit oxidative (CYP) and conjugative (UGT) metabolism using pooled human intestinal and liver microsomes. Buprenorphine was chosen as the model substrate as it is extensively metabolized by CYPs to norbuprenorphine and by UGTs to buprenorphine glucuronide. Chrysin, ginger extract, α-mangostin, pterostilbene and silybin were tested for their inhibition of formation of norbuprenorphine or buprenorphine glucuronide in both intestinal and liver microsomes...
December 5, 2018: Biopharmaceutics & Drug Disposition
Shin-Ichiro Ogawa, Yoshihiko Tunenari, Hiroyuki Kawai, Hiroshi Yamazaki
The metabolic profiles and pharmacokinetics of pemafibrate, a novel selective peroxisome proliferator activated receptor-alpha modulator currently launched as an antidyslipidemic drug, were investigated in vitro using hepatocytes from rats, monkeys, and humans and in vivo in rats and monkeys. Hepatocytes from rats, monkeys, and humans all biotransformed pemafibrate to its demethylated form (M1). The bioavailabilities of pemafibrate in Sprague-Dawley rats and cynomolgus monkeys were 15% and 87%, respectively, after a single oral administration of pemafibrate (1 mg/kg)...
December 5, 2018: Biopharmaceutics & Drug Disposition
Guoqiang Zhang, Yanrong Ma, Dali Xi, Zhi Rao, Xiaohan Sun, Xin An Wu
Metformin is always used the baseline antidiabetic therapy of patients with type 2 diabetes mellitus (T2DM) and hyperuricemia. Metformin excreted into urine through active secretion mediated by rOCTs and rMATE1.The aim of this study was to identify the effects of high uric acid on the disposition and its mechanism. In vivo study, hyperuricemic animal model was induced by intraperitoneal injection of potassium oxonate (250 mg/kg) in rats. Metformin (100mg/kg) was administered orally to investigate the pharmacokinetics in control and hyperuricemic rats, respectively...
November 28, 2018: Biopharmaceutics & Drug Disposition
Yuichi Uwai, Takato Suzuki, Ryota Kondo, Tatsuya Kawasaki, Tomohiro Nabekura
Lithium, administered to patients with bipolar disorders, is mainly excreted in the urine, and tubular reabsorption is involved. This study characterized the renal excretion of lithium in rats subjected to renal ischemia for 60 min or 90 min. After intravenous injection of lithium chloride at 25 mg/kg, the pharmacokinetic parameters of lithium were determined. In sham-operated rats, the renal clearance of lithium was calculated to be 1.49 ml/min/kg, and its ratio to creatinine clearance (fractional excretion) was 43...
November 2018: Biopharmaceutics & Drug Disposition
Zhenxian Zhang, Phillip M Gerk
Phenylephrine (PE) has low and variable oral bioavailability in humans, due in part to presystemic metabolism by sulfation. LS180 cells were used as a model of the human intestinal epithelium to examine phenylephrine metabolism and its inhibition by generally recognized as safe (GRAS) and dietary compounds. Curcumin, zingerone, resveratrol, guaiacol, pterostilbene and isoeugenol significantly inhibited phenylephrine disappearance, while vanillin, propylparaben and eugenol did not. However, when propylparaben was combined with either vanillin or eugenol, the phenylephrine disappearance was significantly inhibited...
November 2018: Biopharmaceutics & Drug Disposition
Sangwoo Ryu, Jonathan J Novak, Roshan Patel, Phillip Yates, Li Di
The effect of low temperature (4 °C) on plasma protein binding and tissue binding was evaluated for the first time using a large set of structurally diverse compounds covering a wide range of physiochemical properties and fraction unbound values. These results show that temperature has little effect on plasma protein binding and tissue binding and that the measured binding values at 4 °C are equivalent, on average, to those at physiological temperature (37 °C). The exception is indomethacin, where binding component(s) changed during long incubation at 37 °C...
November 2018: Biopharmaceutics & Drug Disposition
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