Dosing Adjustments in Cases of Altered Plasma Protein Binding are Most Needed for Drugs with a Volume of Distribution Below 1.3 L/kg.

Background: The present literature offers conflicting views on the importance of changes in plasma protein binding in clinical therapeutics. Furthermore, there are no methods to calculate a new dosing regimen when such changes occur.

Methods: Previous models developed by Balaz et al.

Measurement of free fraction, total concentration and protein binding for testosterone, triiodothyronine and thyroxine.

Measuring the total and free concentrations of hormones is useful, but the technology to do this simultaneously is lacking. A new method offers the ability to measure these parameters concurrently for testosterone, thyroxine and triiodothyronine. The free concentrations showed significant correlations with patients' vital statistics.

Patient-Specific Pharmacokinetics and Dasatinib Nephrotoxicity.

Background: Dasatinib has been associated with nephrotoxicity. We sought to examine the incidence of proteinuria on dasatinib and determine potential risk factors that may increase dasatinib-associated glomerular injury.

Methods: We examined glomerular injury through urine albumin-creatinine ratio (UACR) in 82 patients with chronic myelogenous leukemia who were on tyrosine-kinase inhibitor therapy for at least 90 days.

Comparison of liquid-liquid extraction, microextraction and ultrafiltration for measuring free concentrations of testosterone and phenytoin.

The purpose of the study was to find methods suitable for measuring the free concentrations of testosterone and phenytoin. Sample solutions of the compounds in buffer and human albumin were processed using liquid-liquid extraction, microextraction and ultrafiltration and analyzed by LC-MS/MS. Liquid-liquid extraction with dibutyl phthalate provided complete extraction from buffer solutions and partial extraction from albumin samples.

Impact of Changes in Free Concentrations and Drug-Protein Binding on Drug Dosing Regimens in Special Populations and Disease States.

Over the last few decades, scientists and clinicians have often focused their attention on the unbound fraction of drugs as an indicator of efficacy and the eventual outcome of drug treatments for specific illnesses. Typically, the total drug concentration (bound and unbound) in plasma is used in clinical trials to assess a compound's efficacy. However, the free concentration of a drug tends to be more closely related to its activity and interaction with the body.

Method for Simultaneous Determination of Free Concentration, Total Concentration, and Plasma Binding Capacity in Clinical Samples.

Most quantitative research methods are based on measuring either the total or the free concentration of an analyte in a sample. However, this is often insufficient for the study of complex biological systems. The main objective of this research was to develop new methods for providing more information from samples: the free concentration (C), the total concentration (C), and the plasma binding capacity (PBC).

Influence of Sampling Site and Fluid Flow on the Accuracy of Total Body Clearance Calculation.

Studies have showed that by assuming arteriovenous drug concentrations are homogenous after intravenous injection, the determination of total body clearance based on venous drug concentrations is often inaccurate. This study considers the use of a fluidic pharmacokinetic profile generator where 28 different profile types were generated corresponding to a physiological model with varying sampling sites, administration locations, and fluid flow rates. Clearance was calculated using established equations, commercial software, and recently proposed models.

monitoring of rat brain endocannabinoids using solid-phase microextraction.

Solid-phase microextraction is proposed to measure concentrations of anandamide and 2-arachidonoyl glycerol in live rat brains in response to stress. Solid-phase microextraction fibers were prepared from steel with 1.5 mm extraction coating.

Transdermal sampling of vitamin D and 25-hydroxyvitamin D.

Aim: Transdermal analysis is proposed for vitamin D and its hydroxylated metabolite to overcome problems associated with blood analysis.

Methods: Vitamin D was extracted directly from skin with solid patches and liquid phases. Deuterium-labeled vitamin D was added to the extraction solutions to compensate for variability and accurately determine the rate of transdermal transfer.

Elucidating the role of leptin in systemic inflammation: a study targeting physiological leptin levels in rats and their macrophages.

To elucidate the role of leptin in acute systemic inflammation, we investigated how its infusion at low, physiologically relevant doses affects the responses to bacterial lipopolysaccharide (LPS) in rats subjected to 24 h of food deprivation. Leptin was infused subcutaneously (0-20 μg·kg·h) or intracerebroventricularly (0-1 μg·kg·h). Using hypothermia and hypotension as biomarkers of systemic inflammation, we identified the phase extending from 90 to 240 min post-LPS as the most susceptible to modulation by leptin.

Normalized vitamin D metabolite concentrations are better correlated to pharmacological effects than measured concentrations.

Background: Vitamin D deficiency has been associated with a multitude of diseases, ranging from fractures to cancer. Nearly 99% of vitamin D metabolites are bound to proteins, altering the relationship between concentration and activity.

Methods & Results: Normalized concentrations were calculated and validated using published data regarding the correlation of 25-hydroxyvitamin D with bone mineral density.

Lipoxin A4, a 5-lipoxygenase pathway metabolite, modulates immune response during acute respiratory tularemia.

Respiratory infection with Francisella tularensis (Ft) is characterized by a muted, acute host response, followed by sepsis-like syndrome that results in death. Infection with Ft establishes a principally anti-inflammatory environment that subverts host-cell death programs to facilitate pathogen replication. Although the role of cytokines has been explored extensively, the role of eicosanoids in tularemia pathogenesis is not fully understood.

Evaluation of in vivo solid phase microextraction for minimally invasive analysis of nonvolatile phytochemicals in Amazonian plants.

Introduction: Although solid phase microextraction (SPME) has been used extensively for fingerprinting volatile compounds emitted by plants, there are very few such reports for direct insertion SPME. In this research, direct contact of SPME probes with the interstitial fluid of plants was investigated as a method for phytochemical analysis.

Objective: Medicinal plants from the Amazon have been the source of numerous drugs used in western medicine.

Development of supported liquid-phase microextraction probes for in vivo PK studies.

Background: A new sample preparation method termed supported liquid-phase microextraction is proposed. With this technique, the extraction phase is a liquid immobilized inside the pores of a membrane coated on a solid support.

Methodology: Supported liquid-phase microextraction probes were prepared by coating wires with porous polyacrylonitrile followed by saturation with 1-octanol.

Investigating transdermal delivery of vitamin D3.

Transdermal delivery of therapeutic amounts of vitamin D3 is proposed to overcome its variable oral bioavailability, especially for people who suffer from fat malabsorption. The main challenge for this delivery route is to overcome the barrier properties of skin, especially for very lipophilic compounds such as vitamin D3. In this study, the effect of different penetration enhancers, such as oleic acid, dodecylamine, ethanol, oleic acid in propylene glycol, isopropyl myristate, octyldodecanol, and oleyl alcohol in propylene glycol were evaluated in vitro for their effectiveness in delivering vitamin D3 through polyamide filter, polydimethylsiloxane membrane, and porcine skin.

Naturally occurring hypothermia is more advantageous than fever in severe forms of lipopolysaccharide- and Escherichia coli-induced systemic inflammation.

The natural switch from fever to hypothermia observed in the most severe cases of systemic inflammation is a phenomenon that continues to puzzle clinicians and scientists. The present study was the first to evaluate in direct experiments how the development of hypothermia vs. fever during severe forms of systemic inflammation impacts the pathophysiology of this malady and mortality rates in rats.

Calculation of normalized drug concentrations in the presence of altered plasma protein binding.

Background And Objective: In many clinical situations, measurement of the total drug concentration does not provide the needed information concerning the fraction of unbound drug in plasma, which is available for pharmacodynamic action. To address this, a 'normalized concentration' can be calculated on the basis of the observed total drug concentration and the serum protein level. Up to now, this method has only been applied to phenytoin.

Overview of extraction methods for analysis of vitamin D and its metabolites in biological samples.

In the last decade the scientific and medical community was confronted with a renewed interest in vitamin D and its metabolites, interest prompted by new discoveries regarding the association between members of the vitamin D family and a great number of physiological functions and pathological states. An impressive number of research projects have helped clear the path towards a better understanding of the functions of vitamin D and have resulted in the development of numerous methods of analysis. This review focuses on the various extraction methods used for analysis of vitamin D in research or clinical settings.

Monitoring free drug concentrations: challenges.

Measurement of drug concentrations in biological samples is of utmost importance in many research areas. The information about the amount of drug in a biological sample can be given as either total concentration, which ignores the interaction of the drug with the sample matrix, or as free concentration, which shows the portion of molecules able to diffuse through membranes and exert biological activity. Although the historical trend has been towards determining total concentrations, measurement of free concentrations is becoming more important since it correlates better with pharmacological and toxicological effects.

Determination of free and deconjugated testosterone and epitestosterone in urine using SPME and LC-MS/MS.

Background: A thin sheet of polydimethylsilosane membrane was used as an extraction phase for solid-phase microextraction. Compared with fiber or rod solid-phase microextraction geometries, the thin film exhibited much higher extraction capacity without sacrificing extraction time due to its higher area-to-volume ratio. The analytical method involved direct extraction of unconjugated testosterone (T) and epitestosterone (ET) followed by separation on a C18 column and detection by selected reaction monitoring in positive ionization mode.

In vivo solid-phase microextraction for single rodent pharmacokinetics studies of carbamazepine and carbamazepine-10,11-epoxide in mice.

The use of solid-phase microextraction (SPME) for in vivo sampling of drugs and metabolites in the bloodstream of freely moving animals eliminates the need for blood withdrawal in order to generate pharmacokinetics (PK) profiles in support of pharmaceutical drug discovery studies. In this study, SPME was applied for in vivo sampling in mice for the first time and enables the use of a single animal to construct the entire PK profile. In vivo SPME sampling procedure used commercial prototype single-use in vivo SPME probes with a biocompatible extractive coating and a polyurethane sampling interface designed to facilitate repeated sampling from the same animal.