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Biopharmaceutics & Drug Disposition

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https://www.readbyqxmd.com/read/28092695/absorption-distribution-and-excretion-of-the-anti-tuberculosis-drug-delamanid-in-rats-extensive-tissue-distribution-suggests-potential-therapeutic-value-for-extrapulmonary-tuberculosis
#1
Masakazu Shibata, Yoshihiko Shimokawa, Katsunori Sasahara, Noriaki Yoda, Hiroyuki Sasabe, Mitsunari Suzuki, Ken Umehara
Delamanid (OPC-67683, Deltyba(TM) , nitro-dihydro-imidazooxazoles derivative) is approved for the treatment of adult pulmonary multidrug-resistant tuberculosis. The absorption, distribution, and excretion of delamanid-derived radioactivity were investigated after a single oral administration of (14) C-delamanid at 3 mg/kg to rats. In both male and female rats, radioactivity in blood and all tissues reached peak levels by 8 or 24 hours postdose, and thereafter decreased slowly. Radioactivity levels were 3- to 5-fold higher in lung tissue at time to maximum concentration compared with plasma...
January 16, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28084034/prediction-of-liver-volume-a-population-based-approach-to-meta-analysis-of-pediatric-adult-and-geriatric-populations-an-update
#2
Ben G Small, Bernd Wendt, Masoud Jamei, Trevor N Johnson
: Liver volume is a critical scaling factor for predicting drug clearance in physiologically-based pharmacokinetic modeling and for both donor/recipient graft size estimation in liver transplantation. Accurate and precise estimation of liver volume is therefore essential. The objective here was to extend an existing meta-analysis using a non-linear mixed effects modeling approach for the estimation of liver volume to other race groups and pediatric and geriatric populations. Interrogation of the PubMed® database was undertaken using a text string query to ensure an objective retrieval of liver volume data for the modeling exercise as possible...
January 13, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28039878/quantifying-gut-wall-metabolism-methodology-matters
#3
Oliver J D Hatley, Christopher R Jones, Aleksandra Galetin, Amin Rostami-Hodjegan
Oral administration continues to be the dominant route for dosing of small molecules. Therefore having adequate oral bioavailability remains a key component for the success of drug candidates. Amongst various factors determining the overall bioavailability, the role of the intestinal metabolism is commonly overlooked [1]. Intestinal microsomes are commercially available, analogous to hepatic microsomes which are an essential part of the early drug discovery DMPK (Drug Metabolism and Pharmacokinetics) assessment...
December 30, 2016: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28032362/prioritizing-pharmacokinetic-drug-interaction-precipitants-in-natural-products-application-to-oatp-inhibitors-in-grapefruit-juice
#4
Emily J Johnson, Christina S Won, Kathleen Köeck, 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...
December 29, 2016: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28027412/inhibitory-effect-of-ezetimibe-can-be-prevented-by-an-administration-interval-of-4%C3%A2-h-between-%C3%AE-tocopherol-and-ezetimibe
#5
Shunsuke Nashimoto, Yuki Sato, Yoh Takekuma, Mitsuru Sugawara
Tocopherol is used not only as an ethical drug but also as a supplement. In 2008, Narushima et al. reported that α-tocopherol is partly transported via an intestinal cholesterol transporter, Niemann-Pick C1-Like 1 (NPC1L1). Ezetimibe, a selective inhibitor of NPC1L1, is administered for a long time to inhibit cholesterol absorption and there is a possibility that absorption of α-tocopherol is also inhibited by ezetimibe. In this study, we investigated the influence of ezetimibe on the absorption of α-tocopherol with single administration and long-term administration...
December 27, 2016: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28027398/physiologically-based-pharmacokinetic-predictions-of-intestinal-bcrp-mediated-effect-of-telmisartan-on-the-pharmacokinetics-of-rosuvastatin-in-humans
#6
Soo Hyeon Bae, Wan-Su Park, Seunghoon Han, Gab-Jin Park, Jongtae Lee, Taegon Hong, Sangil Jeon, Dong-Seok Yim
It was recently reported that the Cmax and AUC of rosuvastatin increases when it is coadministered with telmisartan. The aim of this study was to explore the mechanism of the interaction of telmisartan and rosuvastatin. A full-PBPK model of telmisartan was developed, and the rosuvastatin model in Simcyp (version 15)'s drug library was modified to reflect ethnic differences in rosuvastatin exposure. PK characteristics, including intestinal and hepatic transporter / enzyme specificities of telmisartan and rosuvastatin, were incorporated into the PBPK models to simulate a rosuvastatin (20 mg) - telmisartan (80 mg) multiple dose drug interaction study...
December 27, 2016: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28004396/the-absorption-kinetics-of-ketoconazole-plays-a-major-role-in-explaining-the-reported-variability-in-the-level-of-interaction-with-midazolam-exploring-the-interplay-between-formulation-and-inhibition-of-gut-wall-and-liver-metabolism-by-using-different-doses
#7
Bo Liu, H Kim Crewe, Mahmut Ozdemir, Karen Rowland Yeo, Geoffrey Tucker, Amin Rostami-Hodjegan
The impact of different single oral doses of ketoconazole (KTZ) (100, 200 and 400 mg) and of staggering its dosage (400 mg at -12, -2, 0, 2 and 4 h), with respect to the administration of a single 5 mg oral dose of midazolam (MDZ) on the extent of inhibition of the metabolism of the latter, was evaluated in healthy subjects in two separate studies. Escalation of KTZ dosage resulted in 2.3- (1.9), 2.7- (1.7) and 4.2- (2.5) fold increases in the mean AUC(0,12 h) (and Cmax ) values of MDZ. Dose-staggering was associated with 3...
December 21, 2016: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/27977852/unequivocal-evidence-supporting-the-segregated-flow-intestinal-model-that-discriminates-intestine-versus-liver-first-pass-removal-in-pbpk-modeling
#8
K Sandy Pang, Qi Joy Yang, Keumhan Noh
Merits of the segregated flow model (SFM), highlighting the intestine as an inert serosa and active enterocyte c regions, with a smaller fractional (fQ  < 0.3) intestinal flow (QI ) perfusing the enterocyte region, were described. Less drug in the circulation reaches the enterocytes due to the lower flow (fQ QI ) in comparison to drug absorbed from the gut lumen, fostering the idea of route-dependent intestinal removal. The SFM was superior over the traditional model (TM), which views the serosa and enterocytes as a well-mixed tissue perfused by 100% QI ...
December 15, 2016: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/27976813/evaluation-of-drug-efficacy-of-dpp-4-inhibitors-based-on-theoretical-analysis-with-pharmacokinetics-and-pharmacodynamics
#9
Risa Takayanagi, Takumi Uchida, Koji Kimura, Yasuhiko Yamada
Dipeptidyl peptidase-4 (DPP-4) inhibitors are used clinically as therapeutic agents for treatment of diabetes. To determine the rate of DPP-4 inhibition induced by these inhibitors, we used pharmacokinetic and pharmacodynamic parameters to theoretically examine the relationship between the rate of DPP-4 inhibition and clinical efficacy following administration of 4 different DPP-4 inhibitors (sitagliptin, vildagliptin, alogliptin, linagliptin) by focusing on the increase in level of glucagon-like peptide-1 (GLP-1) induced by their administration...
December 15, 2016: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/27976409/oral-drug-absorption-in-pediatrics-the-intestinal-wall-its-developmental-changes-and-current-tools-for-predictions
#10
REVIEW
Jean-Marie Nicolas, François Bouzom, Hugues Chanteux, Anna-Lena Ungell
The dissolution, intestinal absorption and presystemic metabolism of a drug depend on its physicochemical characteristics but also on numerous physiological (e.g. gastrointestinal pH, volume, transit time, morphology) and biochemical factors (e.g. luminal enzymes and flora, intestinal wall enzymes and transporters). Over the last decade, evidence has accumulated indicating that these factors may differ in children and adults resulting in age-related changes in drug exposure and drug response. Thus, drug dosage may require adjustment for the pediatric population to ensure the desired therapeutic outcome and to avoid side-effects...
December 15, 2016: 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
#11
Neha V Maharao, Anand A Joshi, Phillip M Gerk
The present study investigated the potential of generally recognized as safe compounds or dietary substances to inhibit the presystemic metabolism of buprenorphine and increase its oral bioavailability. Using IVIVE, the 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 six and four fold higher intrinsic clearance than glucuronidation in intestine and liver, respectively...
December 7, 2016: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/27925244/the-absorption-enhancement-of-norisoboldine-in-the-duodenum-of-adjuvant-induced-arthritis-rats-involves-the-impairment-of-p-glycoprotein
#12
Cong Duan, Jiao-Mei Guo, Yue Dai, Yu-Feng Xia
Lindera aggregate (Sims) Kosterm root has been used in traditional Chinese medicine for the treatment of rheumatism palsy, dyspepsia and frequent urination for a long history. Norisoboldine (NOR), the main active constituent of this herb drug, possesses outstanding anti-arthritis activity. However, in vivo disposition of NOR has been known to a limited extent, especially under the pathological condition of rheumatoid arthritis (RA). The aim of this study is to investigate whether and how the absorption of NOR is altered in adjuvant-induced arthritis (AIA) rats...
December 7, 2016: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/27925239/physiologically-based-pharmacokinetic-modeling-revealed-minimal-codeine-intestinal-metabolism-in-first-pass-removal-in-rats
#13
Keumhan Noh, Shu Chen, Qi J Yang, K Sandy Pang
The physiologically-based model with segregated flow to the intestine (SFM-PBPK; partial, lower flow to enterocyte region vs. greater flow to serosal region) was found to describe first-pass glucuronidation of morphine (M) to morphine-3β-glucuronide (MG) in rats after intraduodenal (ID) and intravenous (IV) administration better than the traditional model (TM), for which a single intestinal flow perfused the whole of the intestinal tissue. The SFM described a greater extent of intestinal M glucuronidation for ID vs...
December 7, 2016: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/27925234/puerarin-offsets-the-anticoagulation-effect-of-warfarin-in-rats-by-inducing-rcyps-upregulating-vitamin-k-epoxide-reductase-and-inhibiting-thrombomodulin
#14
Beikang Ge, Zhen Zhang, Teddy Taining Lam, Zhong Zuo
PURPOSE: The current study was conducted to investigate the potential pharmacokinetic and pharmacodynamic interactions between warfarin and puerarin which is the most abundant component in Pueraria lobata (Gegen). In vivo and ex vivo rat models were used to reveal the underlying mechanisms of such interactions. METHODS: Apart from one control group, five groups of Sprague-Dawley rats were treated with warfarin, oral puerarin, oral puerarin with warfarin, intravenous puerarin, intravenous puerarin with warfarin...
December 7, 2016: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/27925230/role-of-abc-transporters-in-trans-epithelial-transport-of-vitamin-k-antagonists
#15
Bernadette Espana, Solange Couturier, Caroline Prouillac
Vitamin K antagonists remain (VKAs) the oral anticoagulant of choice of venous thromboembolic disease. These drugs are characterized by a large inter-individual variability requiring frequent dose tailoring. Genetic polymorphisms for cytochrome CYP2C9 and VKORC1 explain some of the variability, especially in warfarin and acenocoumarol responses. The aim of this study is to assess on cell models the role of ABC transporters in the intestinal transfer of the main coumarin derivatives (warfarin, acenocoumarol) and indanedione derivatives (phenindione, fluindione)...
December 7, 2016: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/27882569/selective-reduction-in-the-expression-of-ugts-and-sults-a-novel-mechanism-by-which-piperine-enhances-the-bioavailability-of-curcumin-in-rat
#16
Xiaohui Zeng, Dake Cai, Qiaohuang Zeng, Zhao Chen, Guoping Zhong, Juncheng Zhuo, Haining Gan, Xuejun Huang, Ziming Zhao, Nan Yao, Dane Huang, Chengzhe Zhang, Dongmei Sun, Yuxing Chen
Curcumin (CUR) is known to exert numerous health-promoting effects in pharmacological studies, but its low-bioavailability hinders the development of CUR as a feasible therapeutic agent. Piperine (PIP) has been reported to enhance the bioavailability of CUR, but the underlying mechanism remains poorly understood. In an attempt to find the mechanism by which PIP enhances the bioavailability of CUR, dosage ratio (CUR: PIP) and PIP pre-treatment are hypothesized as key factors for bioavailability improvement in this combination...
November 23, 2016: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/27764535/evaluation-of-species-difference-in-peripheral-lymphocyte-reduction-effect-of-cs-0777-a-sphingosine-1-phosphate-receptor-modulator-based-on-a-pharmacokinetic-pharmacodynamic-model-analysis
#17
Shin-Ichi Inaba, Maki Goto, Kaoru Tanaka-Takanaka, Hisako Tanaka, Wataru Tomisato, Hiroshi Yuita, Hiromi Doi-Komuro, Ryotaku Inoue, Keiko Oshima, Takashi Kagari, Takaichi Shimozato, Takashi Izumi
Pharmacokinetic (PK) and pharmacodynamic (PD) modeling was conducted for the reduction of peripheral lymphocytes after oral administration of CS-0777 to healthy rats, monkeys and experimental autoimmune encephalomyelitis (EAE) induced rats. The phosphorylated active metabolite of CS-0777, M1, is a selective sphingosine 1-phosphate receptor-1 modulator. A linear one- and two-compartment model with a reversible metabolism process characterized the time courses of CS-0777 and M1 concentrations in rats and monkeys, respectively...
December 2016: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/27723114/identification-of-non-reported-bupropion-metabolites-in-human-plasma
#18
Jamie N Connarn, Ruijuan Luo, Jim Windak, Xinyuan Zhang, Andrew Babiskin, Marisa Kelly, Gloria Harrington, Vicki L Ellingrod, Masoud Kamali, Melvin McInnis, Duxin Sun
Bupropion and its three active metabolites exhibit clinical efficacy in the treatment of major depression, seasonal depression and smoking cessation. The pharmacokinetics of bupropion in humans is highly variable. It is not known if there are any non-reported metabolites formed in humans in addition to the three known active metabolites. This paper reports newly identified and non-reported metabolites of bupropion in human plasma samples. Human subjects were dosed with a single oral dose of 75 mg of an immediate release bupropion HCl tablet...
December 2016: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/27704562/efavirenz-does-not-meaningfully-affect-the-single-dose-pharmacokinetics-of-1200%C3%A2-mg-raltegravir
#19
Rajesh Krishna, Lilly East, Patrick Larson, Tara Siringhaus, Lisa Herpok, Crystal Bethel-Brown, Helen Manthos, John Brejda, Michael Gartner
Raltegravir is a human immunodeficiency virus (HIV)-1 integrase strand transfer inhibitor currently marketed at a dose of 400 mg twice daily (BID). Raltegravir for once daily regimen (QD) at a dose of 1200 mg (2 x 600 mg) is under development and offers a new treatment option for HIV-1 infected treatment-naive subjects. Since raltegravir is eliminated mainly by metabolism via an UDP-glucuronosyltransferase (UGT) 1 A1-mediated glucuronidation pathway, co-administration of UGT1A1 inducers may alter plasma levels of raltegravir...
December 2016: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/27696440/atazanavir-increases-the-plasma-concentrations-of-1200-mg-raltegravir-dose
#20
Rajesh Krishna, Lilly East, Patrick Larson, Chandni Valiathan, Kathleen Deschamps, Julie Ann Luk, Crystal Bethel-Brown, Helen Manthos, John Brejda, Michael Gartner
Raltegravir is a human immunodeficiency virus (HIV)-1 integrase strand transfer inhibitor currently marketed at a dose of 400 mg twice-daily (b.i.d.). Raltegravir 1200 mg once-daily (q.d.) (investigational q.d. formulation of 2 × 600 mg tablets; q.d. RAL) was found to be generally well tolerated and non-inferior to the marketed 400 mg b.i.d. dose at 48 weeks in a phase 3 trial. Since raltegravir is eliminated mainly by metabolism via a uridine diphosphate glucuronosyltransferase (UGT) 1A1-mediated glucuronidation pathway, co-administration of UGT1A1 inhibitors may increase the plasma levels of q...
December 2016: Biopharmaceutics & Drug Disposition
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