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Drug Plasma Concentration (drug + plasma_concentration)
Selected AbstractsOn the possibility of self-induction of drug protein bindingJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 10 2010Leonid M. Berezhkovskiy Abstract The equilibrium unbound drug fraction (fu) is an important pharmacokinetic parameter, which influences drug elimination and distribution in the body. Commonly the drug plasma concentration is substantially less then that of drug binding proteins, so that fu can be assumed constant independent of drug concentration. A general consideration of protein binding based on the mass-action law provides that the unbound drug fraction increases with the increase of drug concentration, which is also a usual experimental observation. For several drugs, though, a seemingly unusual sharp decrease of the unbound drug fraction with the increase of total drug concentration (Ro) in the interval 0,<,Ro,,,5,µM was experimentally observed. A possible explanation of this apparently strange phenomenon is presented. The explanation is based on the consideration of a two-step mechanism of drug protein binding. The first step occurs as a drug binding to the site with relatively low affinity. Consequently this binding leads to the activation of a high affinity site, which otherwise is not available for binding. The suggested binding scheme yields the curves for fu dependence on the total drug concentration that are in good agreement with experimental measurements. The interpretation of pharmacokinetic data for the drugs with such unusual concentration dependence of fu appears to be a formidable problem. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:4400,4405, 2010 [source] Consideration of the linear concentration increase of the unbound drug fraction in plasmaJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 2 2009Leonid M. Berezhkovskiy Abstract The concentration of drug in plasma may not necessarily be much less than that of the drug binding proteins, as often considered. Thus the unbound drug fraction could be concentration dependent, which should be taken into account in the interpretation of drug pharmacokinetics and modeling. It is shown that the increase of the unbound drug fraction, fu, can be very accurately considered proportional to the drug plasma concentration for a relatively wide range of concentrations. Equations for the calculation of fu in this linear range are obtained, as well the limiting drug concentration when the linear approximation of fu is applicable. The suggested approach greatly simplifies the calculation of fu and can be ready used in pharmacokinetic calculations and PK-PD models, as well as for the prediction of the change of fu due to the variation of protein concentrations in plasma. Naproxen protein binding in human plasma is considered as an illustration of the method. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:383,393, 2009 [source] The relationships between half-life (t1/2) and mean residence time (MRT) in the two-compartment open body modelBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2004Eyal Sobol Abstract Rationale. In the one-compartment model following i.v. administration the mean residence time (MRT) of a drug is always greater than its half-life (t1/2). However, following i.v. administration, drug plasma concentration (C) versus time (t) is best described by a two-compartment model or a two exponential equation: C=Ae,,t+Be,,t, where A and B are concentration unit-coefficients and , and , are exponential coefficients. The relationships between t1/2 and MRT in the two-compartment model have not been explored and it is not clear whether in this model too MRT is always greater than t1/2. Methods. In the current paper new equations have been developed that describe the relationships between the terminal t1/2 (or t1/2,) and MRT in the two-compartment model following administration of i.v. bolus, i.v. infusion (zero order input) and oral administration (first order input). Results. A critical value (CV) equals to the quotient of (1,ln2) and (1,,/,) (CV=(1,ln2)/(1,,/,)=0.307/(1,,/,)) has been derived and was compared with the fraction (f1) of drug elimination or AUC (AUC-area under C vs t curve) associated with the first exponential term of the two-compartment equation (f1=A/,/AUC). Following i.v. bolus, CV ranges between a minimal value of 0.307 (1,ln2) and infinity. As long as f1 Application of pharmacokinetic modelling to the routine therapeutic drug monitoring of anticancer drugsFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 4 2002Annick Rousseau Abstract Over the last 10 years, proofs of the clinical interest of therapeutic drug monitoring (TDM) of certain anticancer drugs have been established. Numerous studies have shown that TDM is an efficient tool for controlling the toxicity of therapeutic drugs, and a few trials have even demonstrated that it can improve their efficacy. This article critically reviews TDM tools based on pharmacokinetic modelling of anticancer drugs. The administered dose of anticancer drugs is sometimes adjusted individually using either a priori or a posteriori methods. The most frequent clinical application of a priori formulae concerns carboplatin and allows the computation of the first dose based on biometrical and biological data such as weight, age, gender, creatinine clearance and glomerular filtration rate. A posteriori methods use drug plasma concentrations to adjust the subsequent dose(s). Thus, nomograms allowing dose adjustment on the basis of blood concentration are routinely used for 5-fluorouracil given as long continuous infusions. Multilinear regression models have been developed, for example for etoposide, doxorubicin, carboplatin, cyclophosphamide and irinotecan, to predict a single exposure variable [such as area under concentration,time curve (AUC)] from a small number of plasma concentrations obtained at predetermined times after a standard dose. These models can only be applied by using the same dose and schedule as the original study. Bayesian estimation offers more flexibility in blood sampling times and, owing to its precision and to the amount of information provided, is the method of choice for ensuring that a given patient benefits from the desired systemic exposure. Unlike the other a posteriori methods, Bayesian estimation is based on population pharmacokinetic studies and can take into account the effects of different individual factors on the pharmacokinetics of the drug. Bayesian estimators have been used to determine maximum tolerated systemic exposure thresholds (e.g. for topotecan or teniposide) as well as for the routine monitoring of drugs characterized by a very high interindividual pharmacokinetic variability such as methotrexate or carboplatin. The development of these methods has contributed to improving cancer chemotherapy in terms of patient outcome and survival and should be pursued. [source] Drug effect on EEG connectivity assessed by linear and nonlinear couplingsHUMAN BRAIN MAPPING, Issue 3 2010Joan F. Alonso Abstract Quantitative analysis of human electroencephalogram (EEG) is a valuable method for evaluating psychopharmacological agents. Although the effects of different drug classes on EEG spectra are already known, interactions between brain locations remain unclear. In this work, cross mutual information function and appropriate surrogate data were applied to assess linear and nonlinear couplings between EEG signals. The main goal was to evaluate the pharmacological effects of alprazolam on brain connectivity during wakefulness in healthy volunteers using a cross-over, placebo-controlled design. Eighty-five pairs of EEG leads were selected for the analysis, and connectivity was evaluated inside anterior, central, and posterior zones of the scalp. Connectivity between these zones and interhemispheric connectivity were also measured. Results showed that alprazolam induced significant changes in EEG connectivity in terms of information transfer in comparison with placebo. Trends were opposite depending on the statistical characteristics: decreases in linear connectivity and increases in nonlinear couplings. These effects were generally spread over the entire scalp. Linear changes were negatively correlated, and nonlinear changes were positively correlated with drug plasma concentrations; the latter showed higher correlation coefficients. The use of both linear and nonlinear approaches revealed the importance of assessing changes in EEG connectivity as this can provide interesting information about psychopharmacological effects. Hum Brain Mapp, 2010. © 2009 Wiley-Liss, Inc. [source] More pronounced inhibition of cyclooxygenase 2, increase in blood pressure, and reduction of heart rate by treatment with diclofenac compared with celecoxib and rofecoxibARTHRITIS & RHEUMATISM, Issue 1 2006Burkhard Hinz Objective Recent findings suggest that permanent blockade of cyclooxygenase 2 (COX-2) is one factor contributing to the cardiovascular side effects of selective COX-2 inhibitors (coxibs) and nonsteroidal antiinflammatory drugs (NSAIDs). The present study compared the extent and time course of COX-2 inhibition and the effects on cardiovascular parameters (changes in blood pressure and heart rate) between various antirheumatic doses of diclofenac, celecoxib, and rofecoxib in healthy elderly volunteers. Methods A randomized, parallel-group study was conducted in volunteers receiving 75 mg diclofenac twice daily, 200 mg celecoxib twice daily, or 25 mg rofecoxib once daily for 8 days. Blood samples were obtained predose and at specified time points postdose, on days 1 and 8, for assay of drug plasma concentrations and COX-2 inhibition. Lipopolysaccharide-induced prostaglandin E2 synthesis was measured ex vivo as an index of COX-2 activity in human whole blood. Results COX-2 inhibition was significantly less pronounced after treatment with celecoxib and rofecoxib than with diclofenac. Maximal inhibitions after a single dose and at steady state, respectively, were as follows: 99% and 99% with diclofenac, 70% and 81% with celecoxib, and 56% and 72% with rofecoxib. At steady state, only diclofenac caused virtually complete COX-2 inhibition over the whole dose interval, and this corresponded to the highest increase in systolic blood pressure and greatest reduction in heart rate. Conclusion Diclofenac elicited the most pronounced COX-2 inhibition, blood pressure elevation, and suppression of heart rate. It is assumed that the extent and time course of intravascular COX-2 inhibition may determine the differential profile of cardiovascular side effects associated with NSAIDs and coxibs, but this has to be proven in future studies. [source]
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