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rifampicin AND pharmacokinetics

Alexander A Firsov, Maria V Golikova, Elena N Strukova, Yury A Portnoy, Svetlana A Dovzhenko, Mikhail B Kobrin, Stephen H Zinner
To explore if combinations of linezolid (L) with rifampicin (R) are able to restrict Staphylococcus aureus resistance, the enrichment of L- and R-resistant mutants was studied in an in vitro dynamic model. L- and R-resistant mutants were enriched in all single drug treatments. In contrast, L-resistant mutants were not enriched and R-resistant mutants were similar to baseline amounts with only minimal regrowth at the end of the combination treatments. These effects appear to be explained by lowering the mutant prevention concentration (MPC) for L+R combinations (MPCL+R) compared to the MPCs of L and R alone (MPCL and MPCR) and thereby the longer times above MPCL+R (73-100% of the dosing interval for L and 42-58% for R) compared to the times above MPCL (0-44%) and MPCR (0%)...
October 17, 2016: Journal of Chemotherapy
Bella Devaleenal D, Geetha Ramachandran, Soumya Swaminathan
Inter-individual variations in the pharmacokinetics (PK) of anti-TB drugs are known to occur, which could have important therapeutic implications in patient management. Areas covered: We compiled factors responsible for PK variability of anti-TB drugs reported from different settings that would give a better understanding about the challenges of PK variability of anti-TB medications. We searched PubMed data base and Google scholar from 1976 to the present using the key words "Pharmacokinetics", "pharmacokinetic variability", "first-line anti-TB therapy", "Rifampicin", "Isoniazid", "Ethambutol", "Pyrazinamide", "food", "nutritional status", "HIV", "diabetes", "genetic polymorphisms" and "pharmacokinetic interactions"...
October 11, 2016: Expert Review of Clinical Pharmacology
Fuguo Shi, Xiaobing Li, Hong Pan, Li Ding
Rifampicin (RIF) is used in regimens for infections caused by Mycobacteria accompanied by serious adverse reactions. Rifampicin-quinone (RIF-Q) is a major autoxidation product of RIF. It is not clear whether RIF-Q plays a role in RIF induced adverse reactions. Investigation of the systemic exposure of RIF-Q is helpful to better understand the role of RIF-Q in RIF induced adverse reactions. In this study, a simple and reproducible high performance liquid chromatography-mass spectrometry (LC-MS) method involving a procedure to prevent the RIF from oxidation for simultaneous quantification of RIF and RIF-Q in rat plasma has been developed and validated, and applied to elucidate the systemic exposure of RIF-Q in rats...
September 26, 2016: Journal of Pharmaceutical and Biomedical Analysis
M V Varma, E Kimoto, R Scialis, Y Bi, J Lin, H Eng, A S Kalgutkar, A F El-Kattan, A D Rodrigues, L M Tremaine
Montelukast, a leukotriene receptor antagonist commonly prescribed for treatment of asthma, is primarily metabolized by Cytochrome P450 (CYP)2C8, and has been suggested as a probe substrate for investigating CYP2C8 activity in vivo. We evaluated the quantitative role of hepatic uptake transport in its pharmacokinetics and drug-drug interactions (DDIs). Montelukast was characterized with significant active uptake in human hepatocytes, and showed affinity towards organic anion transporting polypeptides (OATPs) in transfected cell systems...
September 20, 2016: Clinical Pharmacology and Therapeutics
Fan Zhang, Hongyan Qin, Yanshu Zhao, Yuhui Wei, Lili Xi, Zhi Rao, Jianping Zhang, Yanrong Ma, Yingting Duan, Xinan Wu
BACKGROUND AND PURPOSE: Long-term medical consequences of cholecystectomy are believed to be uncommon. It has been reported that bile acids (BAs) changed after cholecystectomy. As important signaling molecules, the alternations of BAs might favour the regulatory effect on enzymes and transporters involved in BAs physiological homeostasis at the transcriptional level, which could lead to pharmacokinetic changes of drugs. Here, we determined the effect of cholecystectomy on BAs, relevant enzymes and transporters and pharmacokinetic parameters of rifampicin, and explored the potential mechanisms at the transcriptional regulatory level via nuclear receptors...
September 13, 2016: European Journal of Pharmaceutical Sciences
Tsuyoshi Takahashi, Tatsuyuki Ohtsuka, Yasuhiro Uno, Masahiro Utoh, Hiroshi Yamazaki, Toshiyuki Kume
Cyclosporine A, an inhibitor of hepatic organic anion transporting polypeptides (OATPs), reportedly increased plasma concentrations of probe substrates, although its maximum unbound blood concentrations were lower than the experimental half-maximal inhibitory (IC50 ) concentrations. Pre-incubation with cyclosporine A in vitro before simultaneous incubation with probes has been reported to potentiate its inhibitory effects on recombinant human OATP-mediated probe uptake. In the present study, the effects of cyclosporine A and rifampicin on recombinant cynomolgus monkey OATP-mediated pitavastatin uptake were investigated in pre- and simultaneous incubation systems...
September 7, 2016: Biopharmaceutics & Drug Disposition
Hanna Nylén, Abiy Habtewold, Eyasu Makonnen, Getnet Yimer, Leif Bertilsson, Jürgen Burhenne, Ulf Diczfalusy, Eleni Aklillu
Initiation of efavirenz-based combination antiretroviral therapy (cART) is associated with Vitamin D deficiency, but the risk factors including efavirenz pharmacokinetics for cART-induced severe vitamin D deficiency (SVDD) and the impact of anti-tuberculosis (TB) cotreatment are not explored. We investigated the prevalence of SVDD in HIV and TB-HIV coinfected patients and associated risk factors for treatment-induced SVDD.Treatment-naïve Ethiopian HIV patients with (n = 102) or without (n = 89) TB co-infection were enrolled prospectively and received efavirenz-based cART...
August 2016: Medicine (Baltimore)
Vycke Yunivita, Sofiati Dian, Ahmad Rizal Ganiem, Ela Hayati, Tri Hanggono Achmad, Atu Purnama Dewi, Marga Teulen, Petra Meijerhof-Jager, Reinout van Crevel, Rob Aarnoutse, Rovina Ruslami
High-dose intravenous (i.v.) rifampicin improved the outcome of tuberculous meningitis (TBM) in a previous study. Unfortunately, i.v. rifampicin is not available in many high-endemic settings. This study examined exposures to and safety of higher oral rifampicin doses compared with i.v. rifampicin. Thirty adult Indonesian TBM patients were randomised to rifampicin 750 mg (ca. 17 mg/kg) orally, 900 mg (ca. 20 mg/kg) orally or 600 mg (ca. 13 mg/kg, as used previously) i.v. over 1.5 h for 14 days, combined with other TB drugs...
October 2016: International Journal of Antimicrobial Agents
Sara Neyt, Maarten Vliegen, Bjorn Verreet, Stef De Lombaerde, Kim Braeckman, Christian Vanhove, Maarten Thomas Huisman, Caroline Dumolyn, Ken Kersemans, Fabian Hulpia, Serge Van Calenbergh, Geert Mannens, Filip De Vos
INTRODUCTION: Hepatobiliary transport mechanisms are crucial for the excretion of substrate toxic compounds. Drugs can inhibit these transporters, which can lead to drug-drug interactions causing toxicity. Therefore, it is important to assess this early during the development of new drug candidates. The aim of the current study is the (radio)synthesis, in vitro and in vivo evaluation of a technetium labeled chenodeoxycholic and cholic acid analogue: [(99m)Tc]-DTPA-CDCA and [(99m)]Tc-DTPA-CA, respectively, as biomarker for disturbed transporter functionality...
October 2016: Nuclear Medicine and Biology
A K Hemanth Kumar, T Kannan, V Chandrasekaran, V Sudha, A Vijayakumar, K Ramesh, J Lavanya, S Swaminathan, G Ramachandran
OBJECTIVE: To study the pharmacokinetics of rifampicin (RMP), isoniazid (INH) and pyrazinamide (PZA) in adult tuberculosis (TB) patients and examine factors that influence drug pharmacokinetics. METHODS: Adult TB patients (n = 101) receiving thrice-weekly anti-tuberculosis treatment in the Revised National TB Control Programme (RNTCP) were studied. The study was conducted at steady state after directly observed drug administration. RMP, INH and PZA concentrations were estimated using high-performance liquid chromatography and NAT2 genotyping by real-time polymerase chain reaction...
September 2016: International Journal of Tuberculosis and Lung Disease
Guihong Fu, Chang Zhou, Yuan Wang, Wenhong Fang, Junfang Zhou, Shu Zhao, Licai Ma
In this study with crucian carp (Carassius auratus gibelio), the effect on enrofloxacin (EF) and its metabolite ciprofloxacin (CF) and on the activity of cytochrome P450 1A (CYP1A) and cytochrome P450 3A (CYP3A) was estimated following the oral administration of rifampicin (RIF) (12mg/kg) and β-naphthoflavone (BNF) (12mg/kg), respectively. First, reversed-phase high-performance liquid chromatography (RP-HPLC) was used to detect the pharmacokinetics of EF with continual blood sampling. In RIF-treated, BNF-treated and control groups, the value of the CmaxCF/CmaxEF ratio was 4...
September 2016: Environmental Toxicology and Pharmacology
Chunli Chen, Fatima Ortega, Laura Alameda, Santiago Ferrer, Ulrika S H Simonsson
The current first-line therapy for drug-susceptible tuberculosis consists of rifampicin (RIF), isoniazid (INH), pyrazinamide (PZA) and ethambutol (EMB). In this study, we determined the population pharmacokinetics (PopPK) of RIF, INH, EMB and PZA using original experimental sampling designs for single-dose intravenous (IV) and single- and multiple-dose oral administration studies in the mouse model, and used these PopPK models to develop and evaluate new, more informative sampling designs with the aim of reducing the number of animals required for each drug...
October 10, 2016: European Journal of Pharmaceutical Sciences
Suresh Mallikaarjun, Charles Wells, Carolyn Petersen, Anne Paccaly, Susan E Shoaf, Shiva Patil, Lawrence Geiter
Delamanid is a medicinal product approved for treatment of multidrug-resistant tuberculosis. Three studies were conducted to evaluate the potential drug-drug interactions between delamanid and antiretroviral drugs, including ritonavir, a strong inhibitor of CYP3A4, and selected anti-TB drugs, including rifampin, a strong inducer of cytochrome P450 (CYP) isozymes. Multiple-dose studies were conducted in parallel groups of healthy subjects. Plasma samples were analyzed for delamanid, delamanid metabolite, and coadministered drug concentrations, and pharmacokinetic (PK) parameters were determined...
October 2016: Antimicrobial Agents and Chemotherapy
Soo-Jin Kim, Takashi Yoshikado, Ichiro Ieiri, Kazuya Maeda, Miyuki Kimura, Shin Irie, Hiroyuki Kusuhara, Yuichi Sugiyama
Clopidogrel is reported to be associated with cerivastatin-induced rhabdomyolysis, and clopidogrel and its metabolites are capable of inhibiting CYP2C8 and OATP 1B1 in vitro. The objective of the present study was to identify the mechanism of clopidogrel-mediated drug-drug interactions (DDIs) on the pharmacokinetics of OATP1B1 and/or CYP2C8 substrates in vivo. A clinical cassette small-dose study using OATPs, CYP2C8, and OATP1B1/CYP2C8 probe drugs (pitavastatin, pioglitazone, and repaglinide, respectively) with or without the coadministration of either 600 mg rifampicin (an inhibitor for OATPs), 200 mg trimethoprim (an inhibitor for CYP2C8), or 300 mg clopidogrel was performed, and the area under the concentration-time curve (AUC) ratios (AUCRs) for probe substrates were predicted using a static model...
October 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Roger K Verbeeck, Gunar Günther, Dan Kibuule, Christian Hunter, Tim W Rennie
INTRODUCTION: Tuberculosis (TB) remains one of the world's deadliest communicable diseases. Although cure rates of the standard four-drug (rifampicin, isoniazid, pyrazinamide, ethambutol) treatment schedule can be as high as 95-98 % under clinical trial conditions, success rates may be much lower in less well resourced countries. Unsuccessful treatment with these first-line anti-TB drugs may lead to the development of multidrug resistant and extensively drug resistant TB. The intrinsic interindividual variability in the pharmacokinetics (PK) of the first-line anti-TB drugs is further exacerbated by co-morbidities such as HIV infection and diabetes...
August 2016: European Journal of Clinical Pharmacology
R J Svensson, Ush Simonsson
This is the first clinical implementation of the Multistate Tuberculosis Pharmacometric (MTP) model describing fast-, slow-, and nonmultiplying bacterial states of Mycobacterium tuberculosis. Colony forming unit data from 19 patients treated with rifampicin were analyzed. A previously developed rifampicin population pharmacokinetic (PK) model was linked to the MTP model previously developed using in vitro data. Drug effect was implemented as exposure-response relationships tested at several effect sites, both alone and in combination...
May 2016: CPT: Pharmacometrics & Systems Pharmacology
H McIlleron, H Hundt, W Smythe, A Bekker, J Winckler, L van der Laan, P Smith, H J Zar, A C Hesseling, G Maartens, L Wiesner, A van Rie
SETTING: To assess the revised World Health Organization-recommended dose of 10-20 mg/kg rifampicin (RMP), we studied the steady state pharmacokinetics of RMP in South African children who received standard treatment for drug-susceptible tuberculosis (TB). OBJECTIVE: To determine the formulation effect on the pharmacokinetics of RMP. DESIGN: RMP plasma concentrations were characterised in 146 children (median age 1.4 years, range 0.2-10.2)...
July 2016: International Journal of Tuberculosis and Lung Disease
Caroline Parker
The predictable pharmacokinetic drug interaction between clozapine and rifampicin is listed in most standard reference texts but little detail is given or emphasis on its clinical significance. The interaction is based on theoretical knowledge of both drugs; to date just two case reports have been published. This article describes a third case demonstrating the significance of this interaction. This was potentially devastating for the patient who required an extended psychiatric admission. The enzyme induction was so potent that the dose of clozapine had to be increased approximately sixfold...
June 2016: BJPsych Bulletin
Ben Knippenberg, Madhu Page-Sharp, Sam Salman, Ben Clark, John Dyer, Kevin T Batty, Timothy M E Davis, Laurens Manning
Dried blood spot (DBS) antibiotic assays can facilitate pharmacokinetic (PK)/pharmacodynamic (PD) studies in situations where venous blood sampling is logistically difficult. We sought to develop, validate, and apply a DBS assay for rifampin (RIF), fusidic acid (FUS), and ciprofloxacin (CIP). These antibiotics are considered active against organisms in biofilms and are therefore commonly used for the treatment of infections associated with prosthetic implants. A liquid chromatography-mass spectroscopy DBS assay was developed and validated, including red cell partitioning and thermal stability for each drug and the rifampin metabolite desacetyl rifampin (Des-RIF)...
August 2016: Antimicrobial Agents and Chemotherapy
Nageshwar R Budha, Tao Ji, Luna Musib, Steve Eppler, Mark Dresser, Yuan Chen, Jin Y Jin
BACKGROUND AND OBJECTIVES: Cobimetinib is eliminated mainly through cytochrome P450 (CYP) 3A4-mediated hepatic metabolism in humans. A clinical drug-drug interaction (DDI) study with the potent CYP3A4 inhibitor itraconazole resulted in an approximately sevenfold increase in cobimetinib exposure. The DDI risk for cobimetinib with other CYP3A4 inhibitors and inducers needs to be assessed in order to provide dosing instructions. METHODS: A physiologically based pharmacokinetic (PBPK) model was developed for cobimetinib using in vitro data...
May 25, 2016: Clinical Pharmacokinetics
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