journal
MENU ▼
Read by QxMD icon Read
search

Drug Metabolism and Disposition: the Biological Fate of Chemicals

journal
https://www.readbyqxmd.com/read/28336578/quantitative-prediction-of-cyp3a4-induction-impact-of-measured-free-and-intracellular-perpetrator-concentrations-from-human-hepatocyte-induction-studies-on-drug-drug-interaction-predictions
#1
Yongkai Sun, Paresh P Chothe, Jennifer Sager, Hong Tsao, Amanda Moore, Leena Laitinen, Niresh Hariparsad
Typically, concentration-response curves are generated based upon nominal new chemical entity (NCE) concentrations for in-vitro-to-in-vivo extrapolation of CYP3A4 induction. These data are then used to determine the induction risk of an NCE employing various modeling approaches. The limitation to this practice is that it assumes the hepatocyte culture model to be a static system. In the current study, we assessed whether correcting for; 1) changes in perpetrator concentration in the induction medium during the assay incubation period, 2) perpetrator binding to proteins in the induction medium and 3) non-specific binding of perpetrator can improve the accuracy of CYP3A4 induction predictions...
March 23, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28330858/prolactin-up-regulates-female-predominant-cyp-gene-expressions-and-down-regulates-male-predominant-gene-expressions-in-mice-liver
#2
Yuya Sato, Yoshikatsu Kaneko, Takamasa Cho, Kei Goto, Tadashi Otsuka, Suguru Yamamoto, Shin Goto, Hiroki Maruyama, Ichiei Narita
Prolactin is a polypeptide hormone with over 300 separate biological activities and its serum level is increased during pregnancy and lactation. It has been described that pregnancy and lactation affect drug and steroid metabolism in mice and humans. Several studies reported that pregnancy or lactation influences liver cytochrome P450 (Cyp) expression and its activity, affecting the biosynthesis of steroids and xenobiotics through growth hormone or sex hormones; however, the role of prolactin as the regulator of liver Cyp expression has not been elucidated so far...
March 22, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28325716/coproporphyrin-i-a-fluorescent-endogenous-optimal-probe-substrate-for-abcc2-mrp2-that-is-suitable-for-vesicle-based-mrp2-inhibition-assay
#3
Ravindranath Reddy Gilibili, Sagnik Chatterjee, Pravin Bagul, Kthleen W Mosure, Bokka Venkata Murali, T Thanga Mariappan, Sandhya Mandlekar, Yurong Lai
Inside-out-oriented membrane vesicles are useful tools to investigate whether a compound can be an inhibitor of efflux transporters such as multidrug-resistance associated protein 2 (MRP2). However, because of technical limitations of substrate diffusion and low dynamic uptake windows for interacting drugs used in clinic, estradiol-17β-glucuronide (E17βG) remains the probe substrate frequently used in MRP2 inhibition assays. Here we re-capitulated the sigmoidal kinetics of MRP2 mediated uptake of E17βG, with apparent Km and Vmax values 170 ±17 μM and 1447 ± 137 pmol/mg protein/min, respectively...
March 21, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28320730/prediction-of-the-transporter-mediated-drug-drug-interaction-potential-of-dabrafenib-and-its-major-circulating-metabolites
#4
Harma Ellens, Marta Johnson, Sarah K Lawrence, Cory A Watson, Liangfu Chen, Lauren E Richards-Peterson
The BRAF inhibitor dabrafenib was recently approved for the treatment of certain BRAF V600 mutation-positive tumors, either alone or in combination therapy with the MEK inhibitor trametinib. This article presents the dabrafenib transporter-mediated drug-drug interaction risk assessment, which is currently an important part of drug development, regulatory submission and drug registration. Dabrafenib and its major circulating metabolites (hydroxy-, carboxy- and desmethyl-dabrafenib) were investigated as inhibitors of the clinically relevant transporters Pgp, BCRP, OATP1B1, OATP1B3, OCT2, OAT1 and OAT3...
March 20, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28314825/increased-plasma-exposures-of-conjugated-metabolites-of-morinidazole-in-renal-failure-patients-a-critical-role-of-uremic-toxins
#5
Fandi Kong, Xiaoyan Pang, Kan Zhong, Zitao Guo, Xiuli Li, Dafang Zhong, Xiaoyan Chen
Morinidazole is a 5-nitroimidazole drug. Its sulfate conjugate M7 was a sensitive substrate of organic anion transporter 1 (OAT1) and OAT3, whereas N+-glucuronides M8-1 and M8-2 were only OAT3 substrates. In chronic renal failure (CRF) patients, plasma exposures of the three conjugates increased by 15-fold, which were also found in 5/6 nephrectomized (5/6 Nx) rats in this study. Although the transcriptions of Oat1 and Oat3 in 5/6 Nx rat kidneys decreased by 50%, no difference was observed on the three conjugate uptakes between control and 5/6 Nx rat kidney slices...
March 17, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28289057/applying-stable-isotope-labeled-amino-acids-in-micropatterned-hepatocyte-co-culture-to-directly-determine-the-degradation-rate-constant-for-cyp3a4
#6
Ryan H Takahashi, Sheerin Shahidi-Latham, Susan Wong, Jae H Chang
The rate of enzyme degradation (kdeg) is an important input parameter for the prediction of clinical drug-drug-interactions (DDI) that result from mechanism-based inactivation or induction of cytochrome P450s. Currently, a large range of reported estimates for CYP3A4 enzyme degradation exists, and consequently, large uncertainty exists in steady-state predictions for DDI. In the current investigations, stable isotope labeled amino acids in culture (SILAC) was applied to a long-lived primary human hepatocyte culture, HepatoPac, to directly monitor the degradation of CYP3A4...
March 13, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28283501/phase-ii-conjugates-of-urolithins-isolated-from-human-urine-and-potential-role-of-%C3%AE-glucuronidases-in-their-disposition
#7
Jakub P Piwowarski, Iwona Stanisławska, Sebastian Granica, Joanna Stefańska, Anna K Kiss
In recent years, many xenobiotics derived from natural products have been shown to undergo extensive metabolism by gut microbiota. Ellagitannins, which are high molecular polyphenols, are metabolized to dibenzo[b,d]pyran-6-one derivatives- urolithins. These compounds, in contrast with their parental compounds, have good bioavailability and are found in plasma and urine at micromolar concentrations. In vivo studies conducted for ellagitannin-containing natural products indicate their beneficial health effects towards inflammation and cancer, which are associated with the formation of urolithins...
March 10, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28283500/in-vitro-interactions-of-epacadostat-and-its-major-metabolites-with-human-efflux-and-uptake-transporters-implications-for-pharmacokinetics-and-drug-interactions
#8
Qiang Zhang, Yan Zhang, Jason Boer, Jack G Shi, Peidi Hu, Sharon Diamond, Swamy Yeleswaram
Epacadostat (EPAC) is a first-in-class, orally active inhibitor of the enzyme indoleamine 2,3-dioxygenase 1 (IDO1) and has demonstrated promising clinical activity. In humans, three major plasma metabolites were identified: M9 (a glucuronide-conjugate), M11 (a gut microbiota metabolite), and M12 (a secondary metabolite formed from M11). It is proposed that the biliary excretion of M9, the most abundant metabolite, leads to the enterohepatic circulation of EPAC suggested by the human pharmacokinetics of EPAC...
March 10, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28283499/metabolite-identification-reaction-phenotyping-and-retrospective-drug-drug-interaction-predictions-of-17-deacetylnorgestimate-the-active-component-of-the-oral-contraceptive-norgestimate
#9
Deepak Ahire, Sarmistha Sinha, Barry Brock, Ramaswamy Iyer, Sandhya Mandlekar, Murali Subramanian
Ortho-Tri-Cyclen® (OTC), a two drug cocktail comprising of ethinylestradiol (EE) and norgestimate (13-ethyl-17-acetoxy-18, 19-dinor-17α-pregn-4-en-20yn-3 oxime), is commonly prescribed to avert unwanted pregnancies in women of reproductive age. In vivo, norgestimate undergoes extensive and rapid deacetylation to produce 17-deacetylnorgestimate (NGMN), an active circulating metabolite that likely contributes significantly to norgestimate efficacy. Despite being of primary significance, the metabolism and reaction phenotyping of NGMN have not been previously reported...
March 10, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28270565/midostaurin-a-novel-protein-kinase-inhibitor-for-the-treatment-of-acute-myelogenous-leukemia-insights-from-human-absorption-metabolism-and-excretion-studies-of-a-bddcs-ii-drug
#10
Handan He, Phi Tran, Helen Gu, Vivienne Tedesco, Jin Zhang, Wen Lin, Ewa Gatlik, Kai Klein, Tycho Heimbach
The absorption, metabolism and excretion of midostaurin, a potent class III tyrosine protein kinase inhibitor for acute myelogenous leukemia, were evaluated in healthy subjects. A microemulsion formulation was chosen to optimize absorption. After a 50 mg [14C]midostaurin dose, oral absorption was high (> 90%) and relatively rapid. In plasma, the major circulating components were midostaurin (22%), CGP52421 (32.7%), and CGP62221 (27.7%). Long plasma half-lives were observed for midostaurin (20.3 h), CGP52421 (495 h), and CGP62221 (33...
March 7, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28270564/microsomal-and-cytosolic-scaling-factors-in-dog-and-human-kidney-cortex-and-application-for-in-vitro-in-vivo-extrapolation-of-renal-metabolic-clearance
#11
Daniel Scotcher, Sarah Billington, Jay Brown, Christopher Jones, Colin D A Brown, Amin Rostami-Hodjegan, Aleksandra Galetin
In vitro-in vivo extrapolation of drug metabolism data obtained in enriched preparations of sub-cellular fractions rely upon robust estimates of physiologically relevant scaling factors for prediction of clearance in vivo. The purpose of the current study was to measure the microsomal and cytosolic protein per gram of kidney (MPPGK and CPPGK) in dog and human kidney cortex using appropriate protein recovery markers, and evaluate functional activity of human cortex microsomes. Cytochrome P450 (CYP) content and glucose-6-phosphatase activity were used as microsomal protein markers, whereas glutathione-S-transferase activity was a cytosolic marker...
March 7, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28258069/marmoset-flavin-containing-monooxygenase-3-in-liver-is-a-major-benzydamine-and-sulindac-sulfide-oxygenase
#12
Shotaro Uehara, Makiko Shimizu, Yasuhiro Uno, Takashi Inoue, Erika Sasaki, Hiroshi Yamazaki
Common marmosets (Callithrix jacchus) are potentially primate models for preclinical drug metabolism studies because the molecular characteristics of cytochrome P450 (P450) enzymes have similarities between this species and humans. However, characterization of non-P450 enzymes have not been clarified in marmosets. Here, we report characterization of flavin-containing monooxygenase (FMO) 1-5 identified in marmoset tissues. Marmoset FMO forms shared high amino acid sequence identities (93-95%) and phylogenetic closeness with human homologue FMO forms...
March 3, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28258068/novel-method-to-predict-in-vivo-liver-to-plasma-kpuu-for-oatp-substrates-using-suspension-hepatocytes
#13
Keith Riccardi, Jian Lin, Zhenhong Li, Mark Niosi, Sangwoo Ryu, Wenyi Hua, Karen Atkinson, Rachel E Kosa, John Litchfield, Li Di
The ability to predict human liver-to-plasma unbound partition coefficient (Kpuu) is of great importance to estimate unbound liver concentration, develop PK/PD relationships, predict efficacy and toxicity in the liver, and model drug-drug interaction (DDI) potential for drugs that are asymmetrically distributed into the liver. A novel in vitro method has been developed to predict in vivo Kpuu with good accuracy using cryopreserved suspension hepatocytes in InVitroGRO HI media with 4% BSA. Validation was performed using six OATP substrates with rat in vivo Kpuu data from IV infusion studies where steady state was achieved...
March 3, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28254953/implications-for-metabolite-quantification-by-mass-spectrometry-in-the-absence-of-authentic-standards
#14
Panos Hatsis, Nigel J Waters, Upendra A Argikar
Quantification of metabolites by mass spectrometry in the absence of authentic reference standards or without a radiolabel is often called 'semi-quantitative', which acknowledges that mass spectrometric responses are not truly quantitative. For many researchers, it is tempting to pursue this practice of semi-quantification in early drug discovery and even preclinical development, when radiolabeled ADME studies are being deferred to later stages of drug development. The caveats of quantifying metabolites based on parent drug response are explored in this investigation...
March 2, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28254952/effects-of-microrna-34a-on-the-pharmacokinetics-of-cytochrome-p450-probe-drugs-in-mice
#15
Joseph L Jilek, Ye Tian, Ai-Ming Yu
MicroRNAs (miR) including miR-34a have been shown to regulate nuclear receptor, drug-metabolizing enzyme and transporter gene expression in various cell model systems. However, to what degree miRNAs would affect pharmacokinetics (PK) at the systemic level remains unknown. Additionally, miR-34a replacement therapy represents a new cancer treatment strategy, whereas it is undefined if miR-34a therapeutics would causes any drug-drug interactions (DDI). To address the questions, we developed a practical single-mouse PK approach and investigated the effects of a bioengineered miR-34a agent on the PK of multiple Cytochrome P450 (CYP) probe drugs (midazolam, dextromethorphan, phenacetin, diclofenac, and chlorzoxazone) administered as a cocktail to mouse models...
March 2, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28254951/examination-of-the-human-cytochrome-p4503a4-induction-potential-of-pf-06282999-an-irreversible-myeloperoxidase-inactivator-integration-of-preclinical-in-silico-and-biomarker-methodologies-in-the-prediction-of-the-clinical-outcome
#16
Jennifer Dong, James Gosset, Odette Fahmi, Zhiwu Lin, Jeffrey Chabot, Steven Terra, Vu Le, Kristin Chidsey, Parya Nouri, Albert Kim, Leonard Buckbinder, Amit S Kalgutkar
The propensity for cytochrome P450 (CYP)3A4 induction by 2-(6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide (PF-06282999), an irreversible inactivator of myeloperoxidase, was examined in the present work. Studies using human hepatocytes revealed moderate increases in CYP3A4 messenger RNA (mRNA) and midazolam-1'-hydroxylase activity in a PF-06282999 dose-dependent fashion. At the highest tested concentration of 300 μM, PF-06282999 caused maximal induction in CYP3A4 mRNA and enzyme activity ranging from 56% - 86% and 47% - 72%, respectively, of rifampicin response across the three hepatocyte donor pools...
March 2, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28254950/assessing-the-risk-of-drug-induced-cholestasis-using-unbound-intrahepatic-concentrations
#17
Julia Riede, Birk Poller, Jorg Huwyler, Gian Camenisch
Inhibition of the bile salt export pump (BSEP) has been recognized as a key factor in the development of drug-induced cholestasis (DIC). The risk of DIC in human has previously been assessed using in vitro BSEP inhibition data (IC50) and unbound systemic drug exposure under assumption of the "free drug hypothesis". This concept, however, is unlikely valid as unbound intrahepatic drug concentrations are affected by active transport and metabolism. To investigate this hypothesis we experimentally determined the in vitro liver-to-blood partition coefficients (Kp,uu) for 18 drug compounds using the hepatic Extended Clearance Model (ECM)...
March 2, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28246127/modeling-sex-differences-in-pharmacokinetics-pharmacodynamics-and-disease-progression-effects-of-naproxen-in-rats-with-collagen-induced-arthritis
#18
Xiaonan Li, Debra C DuBois, Richard R Almon, William J Jusko
Naproxen (NPX) is a frequently used nonsteroidal anti-inflammatory drug (NSAID) for rheumatoid arthritis (RA). Lack of quantitative information about the drug exposure-response relationship has resulted in empirical dosage regimens for use of NPX in RA. Few studies included sex as a factor, although RA predominates in women. A pharmacokinetic, pharmacodynamic, and disease progression (PK/PD/DIS) model described the anti-inflammatory effects of NPX in collagen-induced arthritic (CIA) male and female rats. Three groups of rats were included for each sex: healthy animals, CIA controls, and CIA rats given 50 mg/kg single dose NPX intraperitoneally (IP)...
February 28, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28246126/effect-of-disease-related-changes-in-plasma-albumin-on-the-pharmacokinetics-of-naproxen-in-male-and-female-arthritic-rats
#19
Xiaonan Li, Debra C DuBois, Richard R Almon, William J Jusko
Naproxen (NPX) is used in the treatment of rheumatoid arthritis (RA) for alleviation of pain and inflammation. In view of the extensive albumin binding of NPX, this study investigates whether chronic inflammation and sex will influence the physiological albumin concentrations, plasma protein binding, and pharmacokinetics (PK) of NPX. The PK of NPX was evaluated in a rat model of RA (collagen-induced arthritis (CIA) in Lewis rats) and in healthy controls. These PK studies included: 1) NPX in female and male CIA rats that received 10, 25 or 50 mg/kg NPX intraperitoneally (IP), and 2) NPX in healthy female and male rats after IP dosing of NPX at 50 mg/kg...
February 28, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28232382/rna-seq-reveals-age-and-species-differences-of-car-targeted-drug-processing-genes-in-liver
#20
Sunny Lihua Cheng, Theo K Bammler, Julia Yue Cui
The constitutive androstane receptor (CAR/Nr1i3) is an important xenobiotic-sensing nuclear receptor that is highly expressed in liver, and is well known to have species differences. During development, age-specific activation of CAR may lead to modified pharmacokinetics and toxicokinetics of drugs and environmental chemicals, leading to higher risks for adverse drug reactions in newborns and children. The goal of this study was to systematically investigate the age- and species-specific regulation of various drug-processing genes (Li et al...
February 23, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
journal
journal
31615
1
2
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read
×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"