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Biopharmaceutics & Drug Disposition

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https://www.readbyqxmd.com/read/28926871/multiple-organic-cation-transporters-contribute-to-the-renal-transport-of-sulpiride
#1
Liping Li, Yayun Weng, Wei Wang, Mengru Bai, Hongmei Lei, Hui Zhou, Huidi Jiang
Sulpiride, a selective dopamine D2 receptor blocker, is widely used for treatment of schizophrenia, depression, and gastric/duodenal ulcers. Because of the great majority of sulpiride in positive charged at physiological pH7.4, and ~70% of dose recovered in urine in unchanged form after human intravenous administration of sulpiride, we believe transporters play an important role in renal excretion of sulpiride. The aim of the present study was to explore which transporters contribute to the renal disposition of sulpiride...
September 19, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28866862/acetylshikonin-is-a-novel-non-selective-cytochrome-p450-inhibitor
#2
Jong Cheol Shon, Nguyen Minh Phuc, Won Cheol Kim, Jae Kyung Heo, Zhexue Wu, Hyunyoung Lee, Kwang-Hyeon Liu
Acetylshikonin is biologically active compound with anti-cancer and anti-inflammatory activity, which is isolated from the root of Lithospermum erythrorhizoma. We have recently discovered a inhibitory effect of acetylshikonin against CYP2J2 activity. Based on this result, we expanded our study to evaluate the inhibitory effects of acetylshikonin against nine different cytochrome P450 (P450) isoforms in human liver microsomes (HLMs) using substrate cocktails incubation assay. Acetylshikonin showed strong inhibitory effect against all P450s tested with IC50 values of 1...
September 3, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28865089/impact-of-enzalutamide-and-its-main-metabolite-n-desmethyl-enzalutamide-on-pharmacokinetically-important-drug-metabolizing-enzymes-and-drug-transporters
#3
Johanna Weiss, Jutta Kocher, Corina Mueller, Stephanie Rosenzweig, Dirk Theile
Enzalutamide is a new drug against castration-resistant prostate cancer. Recent data indicate profound induction of drug metabolizing enzymes (e.g. cytochrome P450 isoenzyme (CYP) 3A4) but comprehensive in vitro data on other CYP enzymes, drug conjugating enzymes or drug transporters is scarce. Moreover, mechanisms of induction are poorly investigated and the effects of the active metabolite N-desmethyl enzalutamide are unknown. Using LS180 cells as an induction model and quantitative real-time reverse transcription polymerase chain reaction, our study demonstrated a concentration-dependent induction of CYP1A1, CYP1A2, CYP3A5, CYP3A4, UGT1A3, UGT1A9, ABCB1, ABCC2, and ABCG2 mRNA...
September 1, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28849584/5-fluorouracil-treatment-alters-the-expression-of-intestinal-transporters-in-rats
#4
Keiichi Yotsumoto, Takeshi Akiyoshi, Naoki Wada, Ayuko Imaoka, Hisakazu Ohtani
5-Fluorouracil (5-FU), an anticancer drug, causes severe gastrointestinal damage, which may affect the absorption of orally administered drugs including the substrates of intestinal uptake and efflux transporters. In this study, we aimed to quantitatively investigate the effect of 5-FU-induced intestinal damage on the expression of intestinal transporters; P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and peptide transporter 1 (PEPT1) in rats. The rats were treated with 5-FU (30 mg/kg/day, p...
August 28, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28801980/effects-of-proton-pump-inhibitors-and-famotidine-on-elimination-of-plasma-methotrexate-evaluation-of-drug-drug-interactions-mediated-by-organic-anion-transporter-3
#5
Katsuya Narumi, Yu Sato, Masaki Kobayashi, Ayako Furugen, Kumiko Kasashi, Takehiro Yamada, Takanori Teshima, Ken Iseki
Methotrexate (MTX) is an antifolate agent used in the treatment of numerous types of cancer, and eliminated by active tubular secretion via organic anion transporter 3 (OAT3). Gastric antisecretory drugs, such as proton pump inhibitors (PPIs) and histamine H2 receptor antagonists, are widely used among patients with cancer in clinical practice. The aim of the present study was to analyze the potential drug-drug interactions between MTX and gastric antisecretory drugs in high-dose MTX (HD-MTX) therapy. We retrospectively analyzed the impact of PPIs on the plasma MTX concentration on 73 cycles of HD-MTX therapy performed in 43 patients...
August 12, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28758225/metabolism-of-7-ethoxycoumarin-flavanone-and-steroids-by-cytochrome-p450-2c9-variants
#6
Tomohide Uno, Ryosuke Nakano, Kengo Kanamaru, Shinji Takenaka, Yuichi Uno, Hiromasa Imaishi
CYP2C9 is a human microsomal cytochrome P450c (CYP). Much variation in CYP2C9 levels and activity can be attributed to polymorphisms of this gene. Wild-type CYP2C9 and mutants were coexpressed with NADPH-cytochrome P450 reductase in Escherichia coli. The hydroxylase activities toward 7-ethoxycoumarin, flavanone and steroids were examined. Six CYP2C9 variants showed Soret peaks (450 nm) typical of P450 in reduced CO-difference spectra. CYP2C9.38 had the highest 7-ethoxycoumarin de-ethylase activity. All the CYP2C9 variants showed lower flavanone 6-hydroxylation activities than CYP2C9...
July 30, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28744858/d-malate-decreases-renal-content-of-%C3%AE-ketoglutarate-a-driving-force-of-organic-anion-transporters-oat1-and-oat3-resulting-in-inhibited-tubular-secretion-of-phenolsulfonphthalein-in-rats
#7
Yuichi Uwai, Tatsuya Kawasaki, Tomohiro Nabekura
D-Malate inhibits a Krebs cycle enzyme and the tubular transport of α-ketoglutarate, an intermediate of the Krebs cycle and the driving force for rat organic anion transporter 1 (rOAT1) and rOAT3 in the kidney. In this study, we examined effects of D-malate on the rat organic anion transport system. Uptake of 6-carboxyfluorescein by HEK293 cells expressing rOAT1 or rOAT3 was not affected by D-malate and L-malate. Until 60 min after the intravenous injection of phenolsulfonphthalein (PSP), a typical substrate of the renal organic anion transporters, as a bolus to rats, 47...
July 25, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28741675/pharmacokinetics-of-dinalbuphine-sebacate-and-nalbuphine-in-human-after-intramuscular-injection-of-dinalbuphine-sebacate-in-an-extended-release-formulation
#8
Yu En Tien, Wen-Chuan Huang, Hui-Yuan Kuo, Lily Tai, Yow-Shieng Uang, Wendy H Chern, Jin-Ding Huang
Nalbuphine is a semi-synthetic opioid indicated for the relief of moderate to severe pain. Its short half-life requires frequent injections in clinical practices, resulting in greater incidences of adverse events. We have developed a prodrug of nalbuphine, dinalbuphine sebacate (DNS), dissolved in a simple oil-based injectable formulation, which could deliver and maintain effective blood nalbuphine level. An open-label, prospective, two-period study was performed in healthy volunteers to verify the extended blood concentration profile of nalbuphine...
July 25, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28710808/the-application-of-physiologically-based-pharmacokinetic-modelling-to-assess-the-impact-of-antiretroviral-mediated-drug-drug-interactions-on-piperaquine-antimalarial-therapy-during-pregnancy
#9
Olusola Olafuyi, Michael Coleman, Raj K S Badhan
Antimalarial therapy during pregnancy poses important safety concerns due to potential teratogenicity and maternal physiological and biochemical changes during gestation. Piperaquine (PQ) has gained interest for use in pregnancy in response to increasing resistance towards sulfadoxine-pyrimethamine in sub-Saharan Africa. Co-infection with HIV is common in many developing countries, however, little is known about the impact of anti-retroviral (ARV) mediated drug-drug interaction (DDI) on PQ pharmacokinetics during pregnancy...
July 14, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28670738/clinical-assessment-of-the-lag-time-and-tmax-of-pellets-with-controlled-release-of-glucose-in-vitro-in-vivo-comparison-using-13-c-breath-test
#10
David Neumann, Jan Muselík, Dana Sabadková, Sylvie Pavloková, Jana Špirková, Aleš Franc
Maintaining a stable glycemia in diabetes mellitus type 1 requires flexible insulin application and carbohydrates intake to affected individuals. In real life, there might be some situations limiting the insulin-sugar balance control, e.g. night sleep or prolonged sport activities. Glucose pellets with pre-determined time lag between pellet administration and glucose release were developed to mimic "snack eaten in advance". In this article, (13) C-glucose breath test is introduced to translate the laboratory dissolution testing to clinical confirmation of the glucose release pattern using 5 per cent of δ abundance to differentiate (13) C appearance in exhaled breath...
July 3, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28656708/letter-to-the-editor-physiologically-based-pharmacokinetic-predictions-of-intestinal-bcrp-mediated-effect-of-telmisartan-on-the-pharmacokinetics-of-rosuvastatin-in-humans
#11
LETTER
Ruben de Kanter, Christopher Kohl
No abstract text is available yet for this article.
June 28, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28656677/author-s-response-to-letter-to-the-editor-on-physiologically-based-pharmacokinetic-predictions-of-intestinal-bcrp-mediated-effect-of-telmisartan-on-the-pharmacokinetics-of-rosuvastatin-in-humans
#12
https://www.readbyqxmd.com/read/28608515/efavirenz-clearances-in-vitro-and-in-vivo-in-six-cynomolgus-monkeys-associated-with-polymorphic-cytochrome-p450-2c9-and-simulated-by-individual-physiologically-based-pharmacokinetic-models
#13
Masahiro Utoh, Tomonori Miura, Takashi Kusama, Shotaro Uehara, Makiko Shimizu, Yasuhiro Uno, Hiroshi Yamazaki
Cynomolgus monkey cytochrome P450 2C9 (formerly known as P450 2C43) variation was reportedly associated with metabolic clearance of the antiretroviral drug efavirenz in vivo (of three wild-type, one heterozygote, and two homozygote animals), being unlikely in the case of human P450 2B6-dependent efavirenz clearance. In this study, the liver microsomal elimination rates of efavirenz for the same individual animals previously treated with intravenous/oral administrations of efavirenz showed significant reductions associated with the P450 2C9 p...
June 13, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28608480/sgk1-nedd4-2-signaling-pathway-regulates-the-activity-of-human-organic-anion-transporters-3
#14
Haoxun Wang, Guofeng You
Human organic anion transporter 3 (hOAT3) is localized at the basolateral membrane of renal proximal tubule cells and facilitates the renal secretion of numerous clinical drugs, including anti-HIV therapeutics, anti-tumor drugs, antibiotics, antihypertension drugs and anti-inflammatories. The present study explored the role of serum and glucocorticoid-inducible kinase 1 (sgk1) in the regulation of hOAT3. It was shown that over-expression of sgk1 in hOAT3-expressing cells stimulated hOAT3 transport activity by enhancing the transporter expression at the plasma membrane, kinetically reflected as an increased maximal transport velocity Vmax without substantial change in the substrate-binding affinity Km ...
June 13, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28503751/in-vitro-evaluation-of-potential-transporter-mediated-drug-interactions-of-evogliptin
#15
Dae Y Lee, Hye W Chae, Hyun J 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 a 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
#16
Vamshi Krishna Jogiraju, Suvarchala Avvari, Rakesh Gollen, David R Taft
Pregnancy is associated with numerous physiological 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
#17
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
#18
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, the study also evaluated the long-term MBI kinetics of this reaction by pre-incubation for 120 min. Mechanism-based inhibition profiles were obtained using three typical substrates, testosterone, midazolam and nifedipine...
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
#19
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/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
#20
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
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