Of the thousands of novel compounds that a drug discovery project team invents and that bind to the therapeutic target, typically only a fraction of these have sufficient ADME/Tox properties to become a drug product. Understanding ADME/Tox is critical for all drug researchers, owing to its increasing importance in advancing high quality candidates to clinical studies and the processes of drug discovery. If the properties are weak, the candidate will have a high risk of failure or be less desirable as a drug product. This book is a tool and resource for scientists engaged in, or preparing for, the selection and optimization process. The authors describe how properties affect in vivo pharmacological activity and impact in vitro assays. Individual drug-like properties are discussed from a practical point of view, such as solubility, permeability and metabolic stability, with regard to fundamental understanding, applications of property data in drug discovery and examples of structural modifications that have achieved improved property performance. The authors also review various methods for the screening (high throughput), diagnosis (medium throughput) and in-depth (low throughput) analysis of drug properties. * Serves as an essential working handbook aimed at scientists and students in medicinal chemistry * Provides practical, step-by-step guidance on property fundamentals, effects, structure-property relationships, and structure modification strategies * Discusses improvements in pharmacokinetics from a practical chemist's standpoint

Drug-Like Properties: Concepts, Structure Design and Methods from ADME to Toxicity Optimization

Drug-protein binding studies new trends in analytical and experimental methodology

The interactions between polyphenols, especially flavonoids and plasma proteins, have attracted great interest among researchers. Few papers, however, have focused on the structure-affinity relationship of polyphenols on their affinities for plasma proteins. The aim of this review is to give an overview of the research reports on the characterization, influence on the bioactivity, and the structure-affinity relationship for studying the affinities between polyphenols and plasma proteins. The molecular properties that influence the affinities of polyphenols for plasma proteins are the following: 1) One or more hydroxyl groups in the B-ring (e.g., 3',4' dihydroxylated B ring catechol group) of flavonoids enhanced the binding affinities to proteins. However, the hydroxyl group in the C-ring will weaken the binding interaction. 2) The presence of an unsaturated 2,3-bond in conjugation with a 4-carbonyl group, characteristic of flavonols structure, has been associated with stronger binding affinity with plasma proteins; 3) The glycosylation of flavonoids decreases the affinities for plasma proteins by 1-3 orders of magnitude depending on the conjugation site and the class of sugar moiety; 4) The methylation of hydroxyl groups in flavonoids slightly enhanced the affinities for plasma proteins by 2-16 times; 5) The galloylated catechins have higher binding affinities for plasma proteins than do non-galloylated catechins and the pyrogallol-type catechins have higher affinities than do the catechol-type catechins. The affinity of the catechin with 2,3-trans structure was lower than those of the catechin with 2,3-cis structure; 6) The gallotannins with more gallol groups presented a much higher percentage of binding to plasma proteins. α-D-Gallotannin showed a greater affinity for plasma proteins than does the natural stereoisomer, β-D-gallotannin; 7) The binding degree of chlorogenic acid with only one caffeoyl group was lower than the binding degrees of caffeoyl quinic acids with more caffeoyl groups. The methylation of phenolic acid decreased the affinity for BSA.

A review of dietary polyphenol-plasma protein interactions: characterization, influence on the bioactivity, and structure-affinity relationship.

Evaluation of Ultrafiltration for the Free‐Fraction Determination of Single Photon Emission Computed Tomography (SPECT) Radiotracers: β‐CIT, IBF, and Iomazenil

Sodium valproate (valproic acid) has been widely used in the last decade and is now considered a relatively safe and effective anticonvulsant agent. Recently, several investigators have proposed its use in the treatment of anxiety, alcoholism and mood disorders, although these indications require further clinical studies.

Clinical Pharmacokinetics of Valproic Acid — 1988

Equilibrium dialysis, ultrafiltration, and ultracentrifugation were compared to determine their reliability and applicability in the study of binding of an anticonvulsant drug, valproic acid, by plasma proteins. We studied drug binding with pooled serum and with solutions of human serum albumin at physiological concentrations. We compared binding characteristics such as number of binding sites, affinity constants, and percent of binding as measured by each method in the therapeutic range for valproic acid. Results by ultracentrifugation differed from those by equilibrium dialysis and ultrafiltration, which agreed reasonably well with each other.

Equilibrium dialysis, ultrafiltration, and ultracentrifugation compared for determining the plasma-protein-binding characteristics of valproic acid.

We describe a "high-performance" liquid-chromatographic assay for simultaneously determining propisomide and its mono-N-dealkylated metabolite in plasma and urine. After extraction with dichloromethane at alkaline pH, the unchanged drug, its metabolite, and the internal standard are separated by liquid chromatography on a reversed-phase column and the absorbance of the eluate is measured at 254 nm. Selectivity, sensitivity, and reproducibility are excellent. Results are similar to those by gas chromatography for propisomide but, in addition, the metabolite can be simultaneously measured in the same clinical sample. We also report results by this method for blood and plasma samples from a volunteer receiving a single 200-mg dose of propisomide.

J Barré

Papers

Equilibrium dialysis, ultrafiltration, and ultracentrifugation compared for determining the plasma-protein-binding characteristics of valproic acid.

Liquid-chromatographic determination of propisomide and its mono-N-dealkylated metabolite in plasma and urine.