Biomedical subjects

Anne Hersey

Publications and source records attributed to Anne Hersey.

7 recordsLinked to original sources

PubMed2006

Estimation of volume of distribution in humans from high throughput HPLC-based measurements of human serum albumin binding and immobilized artificial membrane partitioning.

The volume of distribution (VD) in humans of 179 known drug molecules (acids, bases, and neutrals) has been modeled using two biomimetic-binding measurements. The phospholipid binding (log K (IAM)) and the plasma protein binding (log K (HSA)) have been calculated from gradient HPLC retention times on immobilized artificial membrane (IAM) and on human serum albumin (HSA) columns, respectively. The log VD values showed good correlation with the compounds' relative binding to IAM and HSA as follows: log VD=0.44 log K (IAM)-0.22 log K (HSA)-0.66; n=179, r2=0.76, s=0.33, and F=272. It was also observed that positively charged molecules bind relatively more to IAM, while negatively charged ones bind more to HSA, in line with the empirical observation that bases tend to have a larger volume of distribution than acids. These results suggest that with the help of these two simple high throughput HPLC-based biomimetic binding measurements an important in vivo drug disposition property can be estimated for use in early drug discovery.

Chemical Phenomena↗

PubMed2003

Blood-brain barrier transport of synthetic adenosine A1 receptor agonists in vitro: structure transport relationships.

Transport of 11 structurally related adenosine A(1) receptor agonists was determined in an in vitro BBB model of brain-capillary-endothelial-cells and astrocytes. Inhibitor S-(4-nitrobenzyl)-6-thioinosine (NBTI) was used to quantify the contribution of the es nucleoside transporter to the overall transport. The N(6)-substituted adenosine analogues N(6)-cyclobutyladenosine (CBA), N(6)-cyclopentyladenosine (CPA) and N(6)-cyclohexyladenosine (CHA) showed concentration-dependent clearance and their transport could be inhibited by NBTI. The V(max) was 1.5+/-0.2 pmol min(-1) and the Km values were 2.2+/-0.2, 1.8+/-0.3 and 15+/-4 microM for CBA, CPA and CHA, respectively. Further chemical modification such as substitution in the C8-position or modification at the ribose-moiety resulted in loss of affinity for the es nucleoside transporter. Transport by passive diffusion was slow with clearances ranging from 0.21+/-0.01 microl min(-1) for 8-(methylamino)-CPA (MCPA) to 1.8+/-0.18 microl min(-1) for 5'-deoxy-CPA (5'dCPA). Regression analysis showed no relationship between transport clearance by passive diffusion and the GTP-shift, a non-linear relationship between the transport clearance by passive diffusion and the dynamic polar surface area (Cl=0.469e(-0.071DPSA); R2=0.88) and a linear relationship between transport clearance and prediction of BBB transport on basis of the Abraham equation (logCl=1.53logBB-1.56; R2=0.83). It is concluded that the transport of synthetic A(1) adenosine derivatives across the blood-brain barrier is generally quite slow. In addition, transport by the es nucleoside transporter may contribute to the transport of certain structurally distinct analogues.

Adenosine↗

PubMed2003

Evaluation of rat intestinal absorption data and correlation with human intestinal absorption.

The absorption of 111 drug and drug-like compounds was evaluated from 111 references based on the ratio of urinary excretion of drugs following oral and intravenous administration to intact rats and biliary excretion of bile duct-cannulated rats. Ninety-eight drug compounds for which both human and rat absorption data were available were selected for correlation analysis between the human and rat absorption. The result shows that the extent of absorption in these two species is similar. For 94% of the drugs the absorption difference between humans and rats is less than 20% and for 98% of drugs the difference is less than 30%. There is only one drug for which human absorption is significantly different from rat absorption. The standard deviation is 11% between human and rat absorption. The linear relationship between human and rat absorption forced through the origin, as determined by least squares regression, is %Absorption (human)=0.997%Absorption (rat) (n=98, SD=11). It is suggested that the absorption in rats could be used as an alternative method to human absorption in pre-clinical oral absorption studies.

Algorithms↗

PubMed2002

On the mechanism of human intestinal absorption.

In order to investigate whether the main step in intestinal absorption in humans is dominated by partition or by diffusion, we have transformed % human intestinal absorption into a first-order rate constant, and have regressed the latter, as logk, against our solvation parameters. The obtained regression coefficients are compared with those for diffusion and partition processes. The coefficients in the logk equation are completely different to those for water/solvent partitions, but are very similar to those for processes (not involving transport through membranes) in which diffusion is the major step. It is suggested that the main step in the absorption process is diffusion through a stagnant mucus layer, together with transfer across the mucusmid R:membrane interface. It is further shown that for strong Bronsted acids and bases, the rate constant for absorption of ionic species is close to that for absorption of the corresponding neutral species, so that to a first approximation the % intestinal absorption can be calculated from properties of the neutral species.

Biological Transport↗

PubMed2002

Rate-limited steps of human oral absorption and QSAR studies.

PURPOSE: To classify the dissolution and diffusion rate-limited drugs and establish quantitative relationships between absorption and molecular descriptors. METHODS: Absorption consists of kinetic transit processes in which dissolution, diffusion, or perfusion processes can become the rate-limited step. The absorption data of 238 drugs have been classified into either dissolution or diffusion rate-limited based on an equilibrium method developed from solubility, dose, and percentage of absorption. A nonlinear absorption model derived from first-order kinetics has been developed to identify the relationship between percentage of drug absorption and molecular descriptors. RESULTS: Regression analysis was performed between percentage of absorption and molecular descriptors. The descriptors used were ClogP, molecular polar surface area, the number of hydrogen-bonding acceptors and donors, and Abraham descriptors. Good relationships were found between absorption and Abraham descriptors or ClogP. CONCLUSIONS: The absorption models can predict the following three BCS (Biopharmaceutics Classification Scheme) classes of compounds: class I, high solubility and high permeability; class III, high solubility and low permeability; class IV, low solubility and low permeability. The absorption models overpredict the absorption of class II, low solubility and high permeability compounds because dissolution is the rate-limited step of absorption.

Administration, Oral↗

PubMedDate not supplied

Quantitative relationship between rat intestinal absorption and Abraham descriptors.

Literature data on the intestinal absorption of 158 drug and drug-like compounds in rats have been collected, and Abraham descriptors for the set of drugs have been calculated using the method of Platts and Abraham et al. Results show that there is a significant relationship between rat intestinal absorption and the Abraham descriptors. In agreement with the human intestinal absorption model, the dominant descriptors in the rat model are the drug hydrogen bond acidity and basicity. In order to compare the absorption models in humans and rats, the absorption model developed from rats was used to predict the absorption in humans. The rat intestinal absorption model is similar to the human absorption model, and data on rats can effectively be used to predict human intestinal absorption.

Animals↗

PubMedDate not supplied

Theoretical prediction of partition coefficients via molecular electrostatic and electronic properties.

Previously published methods for calculation of Abraham's polarity/polarizability and hydrogen bond acidity and basicity descriptors are validated for their ability to predict the various partition coefficients of 80 challenging molecules. As well as this indirect validation, accurate log P predictions are shown to be possible by using directly the fundamental molecular properties used in the calculation of descriptors. From a general point of view, the van der Waals and hydrogen bond interactions present between the solute and the water/solvent system can be represented by charge-based interactions, which are partitioned into a positive and a negative term (Sigma(T)V(Max) and Sigma(T)V(Min)), dipole-based interactions (mu) and induced dipole-based interactions (alpha); further stabilization is possible if solute and solvent densities come into contact and overlap (Sigma(T)E). A discussion is opened on the possibility to extend this set to describe systems with electron donor/acceptor interactions other than hydrogen bonding.

Journal Article↗