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Meng Liu, Jie Yuan, Wen-Juan Hu, Chang-Qiang Ke, Yi-Fan Zhang, Yang Ye, Da-Fang Zhong, Guang-Rong Zhao, Sheng Yao, Jia Liu
The influence of broad-spectrum antibiotics on the pharmacokinetics and biotransformation of major constituents of Shaoyao-Gancao decoction (SGD) in rats was investigated. The pharmacokinetic behaviors of paeoniflorin (PF), albiflorin (AF), liquiritin (LT), isoliquiritin (ILT), liquiritin apioside (LA), isoliquiritin apioside (ILA), and glycyrrhizic acid (GL), seven major constituents of SGD, as well as glycyrrhetinic acid (GA), a major metabolite of GL, were analyzed. A 1-week pretreatment with broad-spectrum antibiotics (ampicillin, metronidazole, neomycin, 1 g L-1 ; and vancomycin, 0...
May 17, 2018: Acta Pharmacologica Sinica
Yasuyuki Ishii, Yuko Ito, Shunji Matsuki, Kasumi Sanpei, Osamu Ogawa, Kenji Takeda, Edgar L Schuck, Naoto Uemura
BFE1224, prodrug of ravuconazole, is a novel, once-daily, oral, triazole antifungal drug, and currently in development for the treatment of onychomycosis. The clinical drug-drug interaction (DDI) potential of BFE1224 with cytochrome P450 (CYP) and transporter was assessed by using two types of cocktails in healthy subjects in separate clinical studies. The CYP and transporter cocktails consisted of caffeine/tolbutamide/omeprazole/dextromethorphan/midazolam used in study 1 and digoxin/rosuvastatin used in study 2...
May 16, 2018: Clinical and Translational Science
Jae H Chang, Xiaolin Zhang, Kirsten Messick, Yi-Chen Chen, Eugene Chen, Jonathan Cheong, Justin Ly
1. OATP inhibitors have been shown to significantly increase the plasma exposure of statins. However, understanding alterations of liver concentration is also important. While modeling has simulated liver concentration changes, availability of experimental data is limited, especially when concerning drug-drug interactions (DDI). The objective of this work was to determine blood and liver concentrations of fluvastatin, lovastatin and pitavastatin, when blocking uptake transporters. 2. In wild-type mouse, rifampin pre-treatment decreased the unbound liver-to-plasma ratio (Kp,uu ) of fluvastatin by 4...
May 16, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Adam Wright, Skye Aaron, Diane L Seger, Lipika Samal, Gordon D Schiff, David W Bates
BACKGROUND: Drug-drug interaction (DDI) alerts in electronic health records (EHRs) can help prevent adverse drug events, but such alerts are frequently overridden, raising concerns about their clinical usefulness and contribution to alert fatigue. OBJECTIVE: To study the effect of conversion to a commercial EHR on DDI alert and acceptance rates. DESIGN: Two before-and-after studies. PARTICIPANTS: 3277 clinicians who received a DDI alert in the outpatient setting...
May 15, 2018: Journal of General Internal Medicine
Alexander P Hughes, Stephan N Salzmann, Okezie K Aguwa, Courtney Ortiz Miller, Roland Duculan, Jennifer Shue, Frank P Cammisa, Andrew A Sama, Federico P Girardi, Ashutosh Kacker, Carol A Mancuso
BACKGROUND: Dysphagia and dysphonia are common complications after anterior cervical spine surgery; however, reported prevalences vary greatly due to a lack of reliable clinical standards for measuring postoperative swallowing and speech dysfunction. The Hospital for Special Surgery Dysphagia and Dysphonia Inventory (HSS-DDI) was developed as a patient-derived, patient-reported instrument to measure dysphagia and dysphonia more accurately after anterior cervical spine surgery than existing indices...
May 16, 2018: Journal of Bone and Joint Surgery. American Volume
Maciej J Zamek-Gliszczynski, Xiaoyan Chu, Jack A Cook, Joseph M Custodio, Aleksandra Galetin, Kathleen M Giacomini, Caroline A Lee, Mary F Paine, Adrian S Ray, Joseph A Ware, Matthias B Wittwer, Lei Zhang
Metformin drug-drug interaction (DDI) studies are conducted during development of drugs that inhibit organic cation transporters and/or multidrug and toxin extrusion proteins (OCTs/MATEs). Monitoring solely changes in systemic exposure, the typical DDI study endpoint appears inadequate for metformin, which is metabolically stable, has poor passive membrane permeability, and undergoes transporter-mediated tissue distribution and clearance. Evaluation of renal clearance, antihyperglycemic effects, and potentially lactate as an exploratory safety marker, can support rational metformin dose adjustment...
May 15, 2018: Clinical Pharmacology and Therapeutics
Issey Takehara, Takashi Yoshikado, Keiko Ishigame, Daiki Mori, Ken-Ichi Furihata, Nobuaki Watanabe, Osamu Ando, Kazuya Maeda, Yuichi Sugiyama, Hiroyuki Kusuhara
PURPOSE: To evaluate association of the dose-dependent effect of rifampicin, an OATP1B inhibitor, on the plasma concentration-time profiles among OATP1B substrates drugs and endogenous substrates. METHODS: Eight healthy volunteers received atorvastatin (1 mg), pitavastatin (0.2 mg), rosuvastatin (0.5 mg), and fluvastatin (2 mg) alone or with rifampicin (300 or 600 mg) in a crossover fashion. The plasma concentrations of these OATP1B probe drugs, total and direct bilirubin, glycochenodeoxycholate-3-sulfate (GCDCA-S), and coproporphyrin I, were determined...
May 10, 2018: Pharmaceutical Research
Amanda King-Ahmad, Sara Clemens, Ragu Ramanathan, Yanhua Zhang, Nancy Raha, Yizhong Zhang, Christopher Holliman, David Rodrigues, Fumin Li
AIM: A validated LC-MS/MS assay for the quantitation of coproporphyrin-I and -III (CP-I, CP-III) in human plasma has been developed to understand the utility of both as possible endogenous biomarkers for organic anion-transporting polypeptides (OATP)-mediated drug-drug interactions (DDIs). MATERIALS AND METHODS:  Human plasma extracts were analyzed for CP-I and CP-III using a 6500+ mass spectrometer. Results: The assay was utilized for plasma samples from a clinical DDI study involving a new chemical entity that presented as an OATP inhibitor in vitro...
May 11, 2018: Bioanalysis
Insook Cho, Yura Lee, Jae-Ho Lee, David W Bates
Objectives: Providing physicians with alerts about potentially harmful drug-drug interactions (DDIs) is only moderately effective due to high alert override rates. To understand high override behavior on DDI alerts, we investigated how physicians respond to DDIs and their behavior patterns and variations. Design: Retrospective system log data analysis and records review (sampling 2% of total overrides). Setting: A large tertiary academic hospital...
May 8, 2018: International Journal for Quality in Health Care
Shinji Yamazaki, Cho-Ming Loi, Emi Kimoto, Chester Costales, Manthena V Varma
Bosutinib is an orally available Src/Abl tyrosine kinase inhibitor indicated for the treatment of patients with Ph+ chronic myelogenous leukemia at a clinically recommended dose of 500 mg once daily. Clinical results indicated that increases in bosutinib oral exposures were supra-proportional at the lower doses (50 to 200 mg) and approximately dose-proportional at the higher doses (200 to 600 mg). Bosutinib is a substrate of CYP3A4 and P-glycoprotein and exhibits pH-dependent solubility with moderate intestinal permeability...
May 8, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Andrej Kastrin, Polonca Ferk, Brane Leskošek
Drug-drug interaction (DDI) is a change in the effect of a drug when patient takes another drug. Characterizing DDIs is extremely important to avoid potential adverse drug reactions. We represent DDIs as a complex network in which nodes refer to drugs and links refer to their potential interactions. Recently, the problem of link prediction has attracted much consideration in scientific community. We represent the process of link prediction as a binary classification task on networks of potential DDIs. We use link prediction techniques for predicting unknown interactions between drugs in five arbitrary chosen large-scale DDI databases, namely DrugBank, KEGG, NDF-RT, SemMedDB, and Twosides...
2018: PloS One
Majda Vrkić Kirhmajer, Viola Macolić Šarinić, Livija Šimičević, Iva Ladić, Krešimir Putarek, Ljiljana Banfić, Nada Božina
Up to the beginning of 2018, a total of eight cases describing rare but clinically important drug interactions between rosuvastatin and ticagrelor which resulted in rhabdomyolysis have been noted in the Global World Health Organization (WHO) adverse drug reaction (ADR) database (VigiBase) as well as in available literature. There are several possible factors which could contribute to the onset of rhabdomyolysis: old age, initially excessive rosuvastatin dose, drug-drug interactions (DDI) on metabolic enzymes (CYPs and UGTs) and drug transporter levels (ABCB1, ABCG2, OATP1B1) and pharmacogenetic predisposition...
May 7, 2018: Basic & Clinical Pharmacology & Toxicology
Anum Munir, Sana Elahi, Nayyer Masood
EGFRs are a vast group of receptor tyrosine kinases playing an important role in a number of tumors, including lungs, head and neck, breast, and esophageal cancers. A couple of techniques are being used in the process of drug design. Drug repositioning or repurposing is a rising idea that consists of distinguishing modern remedial indications for officially existing dynamic pharmaceutical compounds. Here, a novel approach of analyzing drug-drug interaction networks, based on clustering methodology is used to reposition effective compounds against mutant EGFR having G719X, exon 19 deletions/insertions, L858R, and L861Q mutations...
April 27, 2018: Computational Biology and Chemistry
Shinji Yamazaki
A general objective of drug-drug interaction (DDI) studies is to determine whether potential interactions of new molecular entities with concomitantly administered other drugs exist and, if DDIs occur, whether dosage adjustments are required. A typical end point for DDI evaluations is the ratio of area under the plasma concentration-time curve (AUC) of substrate drugs (AUCR), whereas the ratios of maximal plasma concentration (Cmax ) and terminal half-life (t1/2 ) are also important to understand DDI mechanisms (Cmax R and t1/2 R, respectively)...
May 3, 2018: Journal of Clinical Pharmacology
Jing Sun, Xiaozhu Tang, Qianqian Xu, Tao Ge, Daiyin Peng, Weidong Chen
BACKGROUND AND OBJECTIVES: Gambogenic acid (GNA), which possesses diverse antitumor activities both in vitro and in vivo, is regarded as a potential anticancer compound. Cytochrome P450 (CYP) enzymes play an important role in the metabolism of most xenobiotics; constitutive androstane receptor (CAR), a nuclear receptor that might be activated by xenobiotics and associated with the expression of some CYPs. In this study, we determined the effect of GNA on multiple rat liver CYP isoforms (CYP1A2, 2B1, and 2E1) and CAR as well as the potential of GNA to interact with co-administered drugs...
May 2, 2018: European Journal of Drug Metabolism and Pharmacokinetics
Maciej Czerwiński, Immaculate Amunom, Victor Piryatinsky, Hussein Hallak, Yousif Sahly, Oren Bar-Ilan, Paul Bolliger, Merav Bassan
Some biologics can modulate cytokines that may lead to changes in expression of drug-metabolizing enzymes and cause drug-drug interactions (DDI). DDI potential of TV-1106-an albumin-fused growth hormone (GH)-was investigated. In this study, human blood was exposed to recombinant human growth hormone (rhGH) or TV-1106, followed by isolation of the plasma and its application to human hepatocytes. While the treatment of blood with rhGH increased multiple cytokines, treatment of blood with TV-1106 had no effect on any of the nine cytokines tested...
June 2018: Pharmacology Research & Perspectives
Venkatesh Pilla Reddy, Khanh Bui, Graeme Scarfe, Diansong Zhou, Maria Learoyd
We report physiologically based pharmacokinetic-modeling analyses to determine olaparib (tablet or capsule) drug-drug interactions (DDIs). Verified DDI simulations provided dose recommendations for olaparib co-administration with clinically relevant CYP3A4 modulators to eliminate potential risk to patient safety or olaparib efficacy. When olaparib is given with strong/moderate CYP3A inhibitors, the dose should be reduced to 100/150 mg bid (tablet), and 150/200 mg bid (capsule). Olaparib administration is not recommended with strong/moderate CYP3A inducers...
May 1, 2018: Clinical Pharmacology and Therapeutics
Kate Humphrey, Maria Jorina, Marvin Harper, Brenda Dodson, Seung-Yeon Kim, Al Ozonoff
OBJECTIVES: Drug-drug interactions (DDIs) can result in patient harm. DDI alerts are intended to help prevent harm; when the majority of alerts presented to providers are being overridden, their value is diminished. Our objective was to evaluate the overall rates of DDI alert overrides and how rates varied by specialty, clinician type, and patient complexity. METHODS: A retrospective study of DDI alert overrides that occurred during 2012 and 2013 within the inpatient setting described at the medication-, hospital-, provider-, and patient encounter-specific levels was performed at an urban, quaternary-care, pediatric hospital...
May 2018: Hospital Pediatrics
Aarti Sawant-Basak, R Scott Obach, Angela C Doran, Peter Lockwood, Klaas Schildknegt, Hongying Gao, Jessica Mancuso, Susanna Tse, Tom Comery
SAM-760, (2-methyl-1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-benzo[d]imidazole), a 5HT6 antagonist, was investigated in humans for the treatment of Alzheimer's dementia. In liver microsomes and recombinant CYP450 isozymes, SAM-760 was predominantly metabolized by CYP3A (~85%). Based on these observations and an expectation of 5-fold magnitude of interaction with moderate to strong CYP3A inhibitors, a clinical DDI study was performed. In presence of ketoconazole, mean Cmax and AUC0-inf of SAM-760 showed only a modest increase by 30% and 38%, respectively...
April 25, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Kimberly L Garrison, Polina German, Erik Mogalian, Anita Mathias
Several safe and highly-effective directly-acting antiviral drugs for chronic hepatitis C virus (HCV) have been developed and greatly increase the number of treatment options available to successfully treat HCV infection. However, as treatment regimens contain at least two drugs (e.g., sofosbuvir with daclatasvir, simeprevir, ledipasvir, or velpatasvir; elbasvir and grazoprevir) and up to five drugs (ombitasvir/paritaprevir/ritonavir+dasabuvir+ribavirin), the potential for drug-drug interactions (DDI) becomes an important consideration for HCV-infected individuals with comorbidities that require concomitant medications, such as HIV/HCV co-infection or immunosuppression following liver transplantation...
April 25, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
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