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Biopharmaceutics & Drug Disposition

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https://www.readbyqxmd.com/read/28503751/in-vitro-evaluation-of-potential-transporter-mediated-drug-interactions-of-evogliptin
#1
Dae Y Lee, Hye W Chae, Hyunjoo Shim
To date, little is known about the transporter-mediated drug-drug interaction (DDI) potential of evogliptin, a novel DPP-4 inhibitor. The objective of this study was to evaluate the DDI potential of evogliptin using various in vitro assays in transporter-expressing cell lines. After incubating evogliptin with cells overexpressing OAT1, OAT3, OCT2, OATP1B1, and OATP1B3, there was no notable cellular accumulation of evogliptin (fold accumulation, 0.41-1.86). In bidirectional transport assays using Caco-2 cell monolayer, a high efflux ratio (ER, 522) of evogliptin was observed, which was significantly decreased (97...
May 14, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28474821/application-of-physiologically-based-pharmacokinetic-modeling-to-predict-drug-disposition-in-pregnant-populations
#2
Vamshi Krishna Jogiraju, Suvarchala Avvari, Rakesh Gollen, David R Taft
Pregnancy is associated with numerous physiologic changes that influence absorption, distribution, metabolism and excretion. Moreover, the magnitude of these effects changes as pregnancy matures. For most medications, there is limited information available about changes in drug disposition that can occur in pregnant patients, yet most women are prescribed one or more medications during pregnancy. In this investigation, PBPK modeling was used to assess the impact of pregnancy on the pharmacokinetic profiles of three medications (metformin, tacrolimus, oseltamivir) using the Simcyp® Simulator...
May 5, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28474789/functional-characterization-and-tissue-expression-of-marmoset-cytochrome-p450-2e1
#3
Shotaro Uehara, Yasuhiro Uno, Etsuko Tomioka, Takashi Inoue, Erika Sasaki, Hiroshi Yamazaki
Common marmosets (Callithrix jacchus) have attracted increasing attention as a useful small non-human primate model in preclinical research. However, studies on marmoset cytochrome P450 (P450) 2E enzyme have scarcely been conducted. In this study, the full-length cDNA encoding P450 2E1 enzyme was isolated from marmoset livers by reverse transcription (RT)-polymerase chain reaction (PCR). Marmoset P450 2E1 amino acid sequences were highly identical (>88%) to those of cynomolgus monkey and human P450 2E1 enzymes...
May 5, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28425104/inactivation-kinetics-and-residual-activity-of-cyp3a4-after-treatment-with-erythromycin
#4
Yuko Ishikawa, Takeshi Akiyoshi, Ayuko Imaoka, Hisakazu Ohtani
This study aimed to characterize the inactivation kinetics of cytochrome P450 3A4 (CYP3A4) by erythromycin, which involves mechanism-based inhibition (MBI), in detail. In addition to an MBI assay based on the conventional method in which erythromycin and recombinant CYP3A4 were pre-incubated for 15 min, we also evaluated the long-term MBI kinetics of this reaction by pre-incubating for 120 min. MBI profiles were obtained using three typical substrates, testosterone, midazolam, and nifedipine. In the long-term assay, erythromycin evoked a time-dependent biphasic reduction in enzyme activity, but some residual activity (α) was detected in the terminal phase...
April 20, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28374512/pharmacokinetic-analysis-of-inhaled-salmeterol-in-asthma-patients-evidence-from-two-dry-powder-inhalers
#5
Konstantina Soulele, Panos Macheras, Vangelis Karalis
Salmeterol (SAL) is a long-acting β2-adrenergic agonist, which is widely used in the asthma therapy. The aim of this study was to investigate the pharmacokinetics (PK) of inhaled SAL in asthma patients using two different dry powder inhalers. This analysis was based on data from 45 subjects who participated in a two-sequence, four period crossover bioequivalence (BE) study after single administration of the test (T) and reference (R) products. In order to mimic more closely the real treatment conditions, activated charcoal was not co-administered...
April 3, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28294376/influence-of-the-pharmacokinetic-profile-on-the-plasma-glucose-lowering-effect-of-ppar%C3%AE-agonist-pioglitazone-in-wistar-fatty-rats
#6
Akihiko Goto, Yoshihiko Tagawa, Yoshiaki Kimura, Akifumi Kogame, Yuu Moriya, Nobuyuki Amano
Although the mechanism of action for peroxisome proliferator-activated receptor gamma (PPARγ) agonists has been extensively explored, the impact of the pharmacokinetic (PK) profile on the pharmacodynamic (PD) effects of PPARγ agonists has not been elucidated in detail. We evaluated the importance of the PK profile of PPARγ agonist for its PD effect based on population PK/PD analysis. Pioglitazone hydrochloride, the PPARγ agonist, was administered orally to Wistar fatty rats once a day (qd) or once every other day (q2d) as double the amount for the qd treatment...
March 11, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28256717/impact-of-acute-fat-mobilization-on-the-pharmacokinetics-of-the-highly-fat-distributed-compound-tak-357-investigated-by-physiologically-based-pharmacokinetic-pbpk-modeling-and-simulation
#7
Akihiko Goto, Yoshihiko Tagawa, Yuu Moriya, Sho Sato, Yoshiyuki Furukawa, Takeshi Wakabayashi, Tetsuya Tsukamoto, Joost DeJongh, Tamara J van Steeg, Toshiya Moriwaki, Satoru Asahi
In a dog toxicokinetic study, an unusual plasma concentration increase of the highly lipophilic compound TAK-357 was observed 2-weeks after termination of a 2-week repeated dosing in one dog with acute body weight loss. The present study investigates the cause of this increase. A physiologically based pharmacokinetic (PBPK) model was constructed using the rat and dog pharmacokinetic data. Using the constructed model, the TAK-357 concentration profile in case of body weight change was simulated. PBPK model-derived simulation suggested that redistribution from adipose tissues to plasma due to loss of body fat caused the observed concentration increase of TAK-357 in dog plasma...
March 3, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28255999/development-of-a-physiologically-based-pharmacokinetic-model-to-predict-the-effects-of-flavin-containing-monooxygenase-3-fmo3-polymorphisms-on-itopride-exposure
#8
Wangda Zhou, Helen Humphries, Sibylle Neuhoff, Iain Gardner, Eric Masson, Nidal Al-Huniti, Diansong Zhou
Itopride, a substrate of FMO3, has been used for the symptomatic treatment of various gastrointestinal disorders. Physiologically based pharmacokinetic (PBPK) modeling was applied to evaluate the impact of FMO3 polymorphism on itopride pharmacokinetics (PK). The Asian populations within the Simcyp simulator were updated to incorporate information on frequency, activity and abundance of FMO3 enzyme with different phenotypes. A meta-analysis of relative enzyme activities suggested that FMO3 activity in subjects with homozygous Glu158Lys and Glu308Gly mutations (Lys158 and Gly308) in both alleles is ~47% lower than those carrying two wild-type FMO3 alleles...
March 3, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28239866/influence-of-vasomodulators-and-tumor-transplantation-on-the-disposition-of-5-fluorouracil-after-application-to-the-liver-surface-in-rats
#9
Yukinobu Kodama, Miyuki Horishita, Ayako Tokunaga, Hirotaka Miyamoto, Shintaro Fumoto, Hitoshi Sasaki, Junzo Nakamura, Koyo Nishida
This study investigated the effect of epinephrine (a vasoconstrictor) and hydralazine (a vasodilator) on the hepatic disposition of 5-fluorouracil (5-FU) after application to the liver surface in rats. Normal livers were compared with a Walker 256 carcinoma cell tumor model. A cylindrical diffusion cell was attached to the liver surface. 5-FU was added into the diffusion cell in combination with vasomodulators or after pretreatment with epinephrine. After selected treatment times, 5-FU concentrations were assayed at three sites in the excised livers...
February 27, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28207929/optimization-of-intestinal-microsomal-preparation-in-the-rat-a-systematic-approach-to-assess-the-influence-of-various-methodologies-on-metabolic-activity-and-scaling-factors
#10
Oliver J D Hatley, Christopher R Jones, Aleksandra Galetin, Amin Rostami-Hodjegan
The metabolic capacity of the intestine and its importance as the initial barrier to systemic exposure can lead to underestimation of first-pass, and thus overestimation of oral bioavailability. However, the in vitro tools informing estimates of in vivo intestinal metabolism are limited by the complexity of the in vitro matrix preparation and uncertainty with the scaling factors for in vitro to in vivo extrapolation. A number of methods currently exist in the literature for the preparation of intestinal microsomes; however, the impact of key steps in the preparation procedure has not been critically assessed...
April 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28152562/a-comparative-evaluation-of-models-to-predict-human-intestinal-metabolism-from-nonclinical-data
#11
Estelle Yau, Carl Petersson, Hugues Dolgos, Sheila Annie Peters
Extensive gut metabolism is often associated with the risk of low and variable bioavailability. The prediction of the fraction of drug escaping gut wall metabolism as well as transporter-mediated secretion (Fg ) has been challenged by the lack of appropriate preclinical models. The purpose of this study is to compare the performance of models that are widely employed in the pharmaceutical industry today to estimate Fg and, based on the outcome, to provide recommendations for the prediction of human Fg during drug discovery and early drug development...
April 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28032362/prioritizing-pharmacokinetic-drug-interaction-precipitants-in-natural-products-application-to-oatp-inhibitors-in-grapefruit-juice
#12
Emily J Johnson, Christina S Won, Kathleen Köck, Mary F Paine
Natural products, including botanical dietary supplements and exotic drinks, represent an ever-increasing share of the health-care market. The parallel ever-increasing popularity of self-medicating with natural products increases the likelihood of co-consumption with conventional drugs, raising concerns for unwanted natural product-drug interactions. Assessing the drug interaction liability of natural products is challenging due to the complex and variable chemical composition inherent to these products, necessitating a streamlined preclinical testing approach to prioritize precipitant individual constituents for further investigation...
April 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28317174/revisiting-the-role-of-gut-wall-in-the-fate-of-orally-administered-drugs-why-now-and-to-what-effect
#13
EDITORIAL
Amin Rostami-Hodjegan, Ikumi Tamai, K Sandy Pang
No abstract text is available yet for this article.
March 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28214380/application-of-the-mechpeff-model-to-predict-passive-effective-intestinal-permeability-in-the-different-regions-of-the-rodent-small-intestine-and-colon
#14
COMPARATIVE STUDY
D Pade, M Jamei, A Rostami-Hodjegan, D B Turner
A major component of physiologically based pharmacokinetic (PBPK) models is the prediction of the rate and extent of absorption of orally dosed drugs for which knowledge of effective passive intestinal permeability (Peff ) is essential. Single-pass intestinal perfusion (SPIP) studies are used to establish effective permeability in vivo but are difficult to perform in rodents, while mechanistic models to predict drug Peff in rat and mouse have not been published. This work evaluates the predictive performance of the 'MechPeff' model to predict Peff in the rodent intestine based upon knowledge of regional gut physiology and drug-specific physicochemical parameters...
March 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28039878/quantifying-gut-wall-metabolism-methodology-matters
#15
Oliver J D Hatley, Christopher R Jones, Aleksandra Galetin, Amin Rostami-Hodjegan
No abstract text is available yet for this article.
March 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/27925249/inhibition-of-glucuronidation-and-oxidative-metabolism-of-buprenorphine-using-gras-compounds-or-dietary-constituents-supplements-in-vitro-proof-of-concept
#16
Neha V Maharao, Anand A Joshi, Phillip M Gerk
The present study investigated the potential of generally recognized as safe (GRAS) compounds or dietary substances to inhibit the presystemic metabolism of buprenorphine and to increase its oral bioavailability. Using IVIVE, buprenorphine extraction ratios in intestine and liver were predicted as 96% and 71%, respectively. In addition, the relative fraction of buprenorphine metabolized by oxidation and glucuronidation in these two organs was estimated using pooled human intestinal and liver microsomes. In both organs, oxidation appeared to be the major metabolic pathway with a 6 and 4 fold higher intrinsic clearance than glucuronidation in intestine and liver, respectively...
March 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/27757966/p-gp-activity-and-inhibition-in-the-different-regions-of-human-intestine-ex-vivo
#17
COMPARATIVE STUDY
Ming Li, Inge A M de Graaf, Marina H de Jager, Geny M M Groothuis
Although intestinal P-glycoprotein (P-gp) has been extensively studied in vitro and in animals, its activity and the consequences of P-gp inhibition for drug disposition and toxicity in humans are still difficult to accurately extrapolate from these studies. Moreover, existing in vitro models do not take into consideration that the intestine is heterogeneous with respect to P-gp expression. Recently, we reported rat precision-cut intestinal slices (PCIS) as a physiological ex vivo model to study the regional gradient of P-gp activity and inhibition...
March 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/27516347/caco-2-cells-expression-regulation-and-function-of-drug-transporters-compared-with-human-jejunal-tissue
#18
COMPARATIVE STUDY
S Brück, J Strohmeier, D Busch, M Drozdzik, S Oswald
BACKGROUND: Induction or inhibition of drug transporting proteins by concomitantly administered drugs can cause serious drug-drug interactions (DDIs). However, in vitro assays currently available are mostly for studying the inhibitory potential of drugs on intestinal transporter proteins, rather than induction. Therefore, this study investigated the suitability of the frequently used intestinal Caco-2 cell line to predict transporter-mediated DDIs as caused by induction via activation of nuclear receptors...
March 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28207160/pharmacokinetic-interactions-in-mice-between-irinotecan-and-mbl-ii-141-an-abcg2-inhibitor
#19
Emilie Hénin, Mylène Honorat, Jérôme Guitton, Attilio Di Pietro, Léa Payen, Michel Tod
PURPOSE: The chromone derivative MBL-II-141, specifically designed to inhibit ABCG2, was previously demonstrated to combine strong inhibition potency, low toxicity and good efficiency in reversing resistance to irinotecan in a xenografted mouse model. Here, the pharmacokinetic interactions in mice between irinotecan, its active metabolite SN-38 and MBL-II-141 were characterized quantitatively in the blood and in the brain. METHODS: Compartmental models were used to fit the data...
February 16, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28144964/pharmacokinetics-and-protein-binding-of-mpt0b292
#20
Yu-En Tien, Chan-Jung Li, Jing-Ping Liou, Jang-Yang Chang, Jin-Ding Huang
MPT0B292 was identified through screening of compounds able selectively to acetylate α-tubulins in cells and it exhibited potent anti-tumor, anti-angiogenesis and anti-metastatic effects in vitro and in vivo. Because of its poor water solubility, MPT0B292 is difficult to formulate with conventional approaches and hence difficulties are experienced in research practices. MPT0B292 was mixed with albumin in an aqueous solvent to form drug albumin nanoparticles with a size range around 333 nm. Unbound fractions of these nanoparticles were investigated in different or the same albumin concentration solutions...
February 1, 2017: Biopharmaceutics & Drug Disposition
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