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Drug Distribution (drug + distribution)
Selected AbstractsDistribution of ifosfamide and metabolites between plasma and erythrocytesBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 3 2001T. Kerbusch Abstract The distribution of ifosfamide (IF) and its metabolites 2-dechloroethylifosfamide (2DCE), 3-dechloroethylifosfamide (3DCE), 4-hydroxyifosfamide (4OHIF) and ifosforamide mustard (IFM) between plasma and erythrocytes was examined in vitro and in vivo. In vitro distribution was investigated by incubating blood with various concentrations of IF and its metabolites. In vivo distribution of IF, 2DCE, 3DCE and 4OHIF was determined in 7 patients receiving 9 g/m2/72 h intravenous continuous IF infusion. In vitro distribution equilibrium between erythrocytes and plasma was obtained quickly after drug addition. Mean (±sem) in vitro and in vivo erythrocyte (e),plasma (p) partition coefficients (Pe/p) were 0.75±0.01 and 0.81±0.03, 0.62±0.09 and 0.73±0.05, 0.76±0.10 and 0.93±0.05 and 1.38±0.04 and 0.98±0.09 for IF, 2DCE, 3DCE and 4OHIF, respectively. These ratios were independent of concentration and unaltered with time. The ratios of the area under the erythrocyte and plasma concentration--time curves (AUCe/p) were 0.96±0.03, 0.87±0.07, 0.98±0.06 and 1.34±0.39, respectively. A time- and concentration-dependent distribution--equilibrium phenomenon was observed with the relative hydrophilic IFM. It is concluded that IF and metabolites rapidly reach distribution equilibrium between erythrocytes and plasma; the process is slower for IFM. Drug distribution to the erythrocyte fraction ranged from about 38% for 2DCE to 58% for 4OHIF, and was stable over a wide range of clinically relevant concentrations. A strong parallelism in the erythrocyte and plasma concentration profiles was observed for all compounds. Thus, pharmacokinetic assessment using only plasma sampling yields direct and accurate insights into the whole blood kinetics of IF and metabolites and may be used for pharmacokinetic,pharmacodynamic studies. Copyright © 2001 John Wiley & Sons, Ltd. [source] Drug,liposome distribution phenomena studied by capillary electrophoresis-frontal analysisELECTROPHORESIS, Issue 16 2008Jesper Østergaard Professor Abstract The potential of using CE frontal analysis (CE-FA) for the study of low-molecular-weight drug,liposome interactions was assessed. The interaction of bupivacaine, brompheniramine, chlorpromazine, imipramine, and ropivacaine with net negatively charged 80/20,mol% 1-oleoyl-2-palmitoyl- sn -glycero-3-phosphocholine/egg yolk phosphatidic acid liposome suspensions in HEPES buffer at pH,7.4 was investigated. The fraction of free drug as a function of lipid concentration was measured and apparent liposome , buffer distribution coefficients were determined for the basic drug substances. The distribution coefficients increased in the order ropivacaine, bupivacaine, brompheniramine, imipramine, and chlorpromazine. The developed CE method was relatively fast allowing estimates of drug,liposome affinity to be obtained within 15,min. CE-FA may have the potential to become a valuable tool for the characterization of drug,liposome interactions in relation to estimation of drug lipophilicity and for the evaluation of drug distribution in liposomal drug delivery systems. [source] Blood,brain barrier damage and brain penetration of antiepileptic drugs: Role of serum proteins and brain edemaEPILEPSIA, Issue 4 2009Nicola Marchi Summary Purpose:, Increased blood,brain barrier (BBB) permeability is radiologically detectable in regions affected by drug-resistant epileptogenic lesions. Brain penetration of antiepileptic drugs (AEDs) may be affected by BBB damage. We studied the effects of BBB damage on brain distribution of hydrophilic [deoxy-glucose (DOG) and sucrose] and lipophilic (phenytoin and diazepam) molecules. We tested the hypothesis that lipophilic and hydrophilic drug distribution is differentially affected by BBB damage. Methods:, In vivo BBB disruption (BBBD) was performed in rats by intracarotid injection of hyperosmotic mannitol. Drugs (H3-sucrose, 3H-deoxy-glucose, 14C-phenytoin, and C14-diazepam) or unlabeled phenytoin was measured and correlated to brain water content and protein extravasation. In vitro hippocampal slices were exposed to different osmolarities; drug penetration and water content were assessed by analytic and densitometric methods, respectively. Results:, BBBD resulted in extravasation of serum protein and radiolabeled drugs, but was associated with no significant change in brain water. Large shifts in water content in brain slices in vitro caused a small effect on drug penetration. In both cases, total drug permeability increase was greater for lipophilic than hydrophilic compounds. BBBD reduced the amount of free phenytoin in the brain. Discussion:, After BBBD, drug binding to protein is the main controller of total brain drug accumulation. Osmotic BBBD increased serum protein extravasation and reduced free phenytoin brain levels. These results underlie the importance of brain environment and BBB integrity in determining drug distribution to the brain. If confirmed in drug-resistant models, these mechanisms could contribute to drug brain distribution in refractory epilepsies. [source] Drug metabolism and disposition in childrenFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 3 2003M. Strolin Benedetti Abstract Key factors undergoing maturational changes accounting for differences in drug metabolism and disposition in the pediatric population compared with adults are reviewed. Gastric and duodenal pH, gastric emptying time, intestinal transit time, bacterial colonization and probably P-glycoprotein are important factors for drug absorption, whereas key factors explaining differences in drug distribution between the pediatric population and adults are membrane permeability, plasma protein concentration and plasma protein characteristics, endogenous substances in plasma, total body and extracellular water, fat content, regional blood flow and probably P-glycoprotein, mainly that present in the gut, liver and brain. As far as drug metabolism is concerned, important differences have been found in the pediatric population compared with adults both for phase I enzymes [oxidative (e.g. cytochrome CYP3A7 vs. CYP3A4 and CYP1A2), reductive and hydrolytic enzymes] and phase II enzymes (e.g. N -methyltransferases and glucuronosyltransferases). Finally, key factors undergoing maturational changes accounting for differences in renal excretion in the pediatric population compared with adults are glomerular filtration and tubular secretion. It would be important to generate information on the developmental aspects of renal P-glycoprotein and of other renal transporters as done and still being done with the different isozymes involved in drug metabolism. [source] Lipophilic cationic drugs increase the permeability of lysosomal membranes in a cell culture system,JOURNAL OF CELLULAR PHYSIOLOGY, Issue 1 2010Johannes Kornhuber Lysosomes accumulate many drugs several fold higher compared to their extracellular concentration. This mechanism is believed to be responsible for many pharmacological effects. So far, uptake and release kinetics are largely unknown and interactions between concomitantly administered drugs often provoke mutual interference. In this study, we addressed these questions in a cell culture model. The molecular mechanism for lysosomal uptake kinetics was analyzed by live cell fluorescence microscopy in SY5Y cells using four drugs (amantadine, amitriptyline, cinnarizine, flavoxate) with different physicochemical properties. Drugs with higher lipophilicity accumulated more extensively within lysosomes, whereas a higher pKa value was associated with a more rapid uptake. The drug-induced displacement of LysoTracker was neither caused by elevation of intra-lysosomal pH, nor by increased lysosomal volume. We extended our previously developed numerical single cell model by introducing a dynamic feedback mechanism. The empirical data were in good agreement with the results obtained from the numerical model. The experimental data and results from the numerical model lead to the conclusion that intra-lysosomal accumulation of lipophilic xenobiotics enhances lysosomal membrane permeability. Manipulation of lysosomal membrane permeability might be useful to overcome, for example, multi-drug resistance by altering subcellular drug distribution. J. Cell. Physiol. 224:152,164, 2010 © 2010 Wiley-Liss, Inc. [source] A valid equation for the well-stirred perfusion limited physiologically based pharmacokinetic model that consistently accounts for the blood,tissue drug distribution in the organ and the corresponding valid equation for the steady state volume of distributionJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 1 2010Leonid M. Berezhkovskiy Abstract A consistent account of the assumptions of the well-stirred perfusion limited model leads to the equation for the organ tissue that does not coincide with that often presented in books and papers. The difference in pharmacokinetic profiles calculated by the valid and the commonly used equations could be quite significant, particularly due to contribution of the organs with relatively large perfusion volume, and especially for drugs with small tissue,plasma partition coefficient and high blood,plasma concentration ratio. Application of the valid equation may result in much faster initial drop of drug plasma concentration time curve and significantly longer terminal half-life, especially for low extraction ratio drugs. An equation for the steady state volume of distribution consistent with the well-stirred model described by the valid equation is provided. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:475,485, 2010 [source] Determination of the In Vitro Susceptibility of Feline Tritrichomonas foetus to 5 Antimicrobial AgentsJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 5 2007Elizabeth J. Kather Background: The nitroimidazole, ronidazole, has been demonstrated to have in vitro and in vivo activity against the protozoan Tritrichomonas foetus in cats. The purpose of this study was to evaluate the in vitro susceptibility of feline T foetus isolates obtained from naturally infected cats to 5 antimicrobial agents and to compare the in vitro time kill of ronidazole and metronidazole. Hypothesis: We hypothesized that nitroimidazoles have in vitro activity against T foetus, whereas furazolidone, omeprazole, and paromomycin do not. Animals: Fecal specimens were cultured from 4 naturally infected Bengal cats with a history of T foetus -associated diarrhea. Methods: A 24-hour susceptibility assay was performed on all 4 isolates for the 5 antimicrobial agents. A time-kill microdilution method was performed on 2 isolates for metronidazole and ronidazole. Results: Paromomycin and omeprazole showed no in vitro effect at concentrations ±80 ,g/mL. There was no significant difference in 24-hour susceptibilities among metronidazole, ronidazole, and furazolidone. In addition, only the results of the highest concentration tested (80 ,g/mL) and concentrations of 1.25 and 2.5 ,g/mL revealed significant differences in the rate of trophozoite killing, with ronidazole having a faster reduction in trophozoite survival. Conclusions and Clinical Importance: Time-kill assays demonstrated ronidazole had a higher lethal activity compared with metronidazole. These findings contrast with a previously published report and may reflect strain variation, different methodologies, or both. The lack of clinical response seen with metronidazole administration to treat feline trichomoniasis may not reflect inherent resistance but rather in vivo events involving drug distribution and pharmacokinetics. [source] Clinically relevant drug interactions of current antifungal agentsMYCOSES, Issue 2 2010Paul O. Gubbins Summary Antifungal agents are often prescribed in critically ill patients who are receiving many other medications. When using systemic antifungals, clinicians may possess susceptibility data and they are typically aware of the potential toxicity of these agents. However, the myriad of potential drugs that antifungal agents can interact with is daunting and can be confusing. This article reviews the pharmacokinetic properties of antifungal agents and their clinically relevant drug interactions. The antifungal agents differ markedly in their pharmacokinetic properties and in how they interact with other medicines. The amphotericin B formulations interact with other medicines primarily by reducing their renal elimination or producing additive toxicities. The azoles interact with other medicines primarily by inhibiting biotransformation or by affecting drug distribution and elimination. The echinocandins have the lowest propensity to interact with other medicines. The clinical relevance of antifungal,drug interactions varies substantially. While certain interactions are benign and result in little or no untoward clinical outcomes, others can produce significant toxicity or compromise efficacy if not properly managed through monitoring and dosage adjustment. However, certain interactions produce significant toxicity or compromise efficacy to such an extent that they cannot be managed and the particular combination of antifungal and interacting medicine should be avoided. [source] Review of case reports of inadvertent intrathecal administration of vincristine: Recommendations to reduce occurrenceASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY, Issue 2 2007Peter J GILBAR Abstract Vincristine has been in clinical use for over 40 years with initial publication of the results from successful trials in 1962. Catastrophic neurotoxicity has been associated with the administration of vincristine directly into the cerebrospinal fluid (CSF). Since the first case in 1968 there have been numerous other instances, of which 23 have been reported in the literature. Of these cases 18 resulted in death. The most prominent damage on autopsy was generally in the spinal cord, brain stem and cerebellum, with severity tending to be greater in the neurons adjacent to the CSF. Fatalities appeared due to a progressive ascending myeloencephalopathy. Early recognition and immediate treatment with CSF drainage and intrathecal exchange appears to be the only intervention that has improved patient survival. The volume of injection, dose and time from the incident until the ventriculo-lumbar washout appear critical, as these factors might contribute to the extent of drug distribution in the CNS. Although several antidotes for vincristine have been suggested, including folinic acid and glutamic acid, supportive evidence for their effectiveness is scant. Several recommendations regarding prevention of this catastrophic event have been proposed. [source] High dose methotrexate population pharmacokinetics and Bayesian estimation in patients with lymphoid malignancyBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 8 2009Ye Min Abstract The purpose of present study was to develop a population pharmacokinetic model of high dose methotrexate (HD-MTX) infusion in patients with lymphoid malignancy, to investigate the biological and clinical covariates related to the drug distribution and elimination. It is also the purpose to propose a limited sampling strategy (LSS) for the estimation of the time above the threshold (0.2,µmol·L,1). A total 82 patients with lymphoid malignancy were involved in the study. A pharmacokinetic model was developed using nonlinear mixed-effect model. The influence of demographic characteristics, biological factors, and concurrent administration were investigated. The final predictive performance was validated by bootstrap and cross-validation. Bayesian estimation was evaluated. The pharmacokinetics of HD-MTX was described by a two-compartment model. The pharmacokinetic parameters and the inter-individual variability were as follows: the clearance CL, 7.45,L·h,1 (inter-individual variability 50.6%), the volume of the central and peripheral compartment V1, 25.9,L (22.5%), V2, 9.23,L (97.8%), respectively, and the intercompartmental clearance Q, 0.333,L·h,1 (70.4%). The influence of serum creatinine on CL and weight on V1 was retained in the final model. The protocol involved one sampling time at 44,h after the start of the infusion, allowing one to predict the time at which the MTX concentration reached the expected threshold (0.2,µmol·L,1). Serum creatinine and weight showed significant influence on methotrexate CL and V1, respectively. Furthermore, a Bayesian estimation based on the covariates and 44,h sample was developed, allowing prediction of the individual methotrexate pharmacokinetic parameters and the time to 0.2,µmol·L,1. Copyright © 2009 John Wiley & Sons, Ltd. [source] Myocardium distribution of sertindole and its metabolite dehydrosertindole in guinea-pigsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2006Mireille Canal-Raffin Abstract Sertindole, like other atypical antipsychotics, has been shown to increase the action potential duration and QT interval in a concentration dependent manner, in in vitro electrophysiological studies. However, this does not always translate into increased duration of the QT interval, increased risk of torsade de pointes or sudden death in clinical practice. The reasons for these apparent discrepancies are unclear and many studies have underscored the importance of the interpretation of in vitro electrophysiological data in the context of other pharmacodynamic (e.g. cardiac ion channels target, receptor affinity) and pharmacokinetic parameters (total plasma drug concentration and drug distribution). To address the possible relevance of the concentrations used in experimental studies, the myocardium distribution of sertindole and its metabolite was determined after single and repeated intraperitoneal administration to guinea-pigs. The data suggest that the plasma concentration appears to predict the concentration in the myocardium and that the myocardium concentrations of sertindole are 3.1 times higher than plasma concentrations. Using these data, the relevance of in vitro electrophysiological studies to clinical plasma concentrations has been appraised. Copyright © 2006 John Wiley & Sons, Ltd. [source] The assessment of topical nasal drug distributionCLINICAL OTOLARYNGOLOGY, Issue 3 2004R. Aggarwal The mainstay of treatment of chronic rhinosinusitis is through the administration of topical nasal drugs. The delivery and intranasal distribution of these is therefore of potential clinical significance. Until there is progress in the nasal drug distribution assessment methodology, it will be difficult to improve topical nasal drug delivery, which is known to be suboptimal in many ways. This study reviews intranasal drug delivery assessment methods, the present knowledge and explores future directions for research. [source] A preliminary analysis and model of prostate injection distributionsTHE PROSTATE, Issue 4 2006Scott L. Chowning Abstract PURPOSE Understanding the internal dynamics of prostate injections, particularly injection pattern distribution is a key step to developing new therapies for prostate disease that may be best served with a direct injection approach. Due to excellent properties involving liquid contrast agents, MRI can be used for targeting and monitoring of injections into organs and tissues. MATERIALS AND METHODS Eleven intraprostatic injections were performed in vivo with canines using a custom transrectal guiding and imaging system for use in a standard 1.5 T MR scanner. In addition, 25 injections were performed on excised cadaveric human prostates, using a MedRad SpectrisÔ injector system. MRI was used to guide the injections and monitor intraparenchymal injection distribution. RESULTS T1 and T2-weighted MR images were correlated with histology to produce three-dimensional data sets that can be used to analyze trends in injection patterns. This analysis was used to develop strategies for injection prediction such as gadolinium preinjections and diffusion-weighted imaging guidance. In addition, a rough model of prostate injections is described, and a preliminary injection guide is developed that takes into account the individual clinician's goals for therapy. CONCLUSIONS MR visualization of injected therapeutic agents allows for prediction and monitoring of drug distributions, possibly improving efficacy and reducing side effects. Injection analysis and modeling may be used to assist in optimizing clinical treatments that require or would benefit from focal parenchymal injections into the prostate. © 2005 Wiley-Liss, Inc. [source] | |||||||||||||