Joelle Le

Rate-limited steps of human oral absorption and QSAR studies

AbstractPurpose. To classify the dissolution and diffusion rate-limited drugs and establish quantitative relationships between absorption and molecular descriptors.nMethods. 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.nResults. 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.nConclusions. 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.

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.

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.

The solubility of gases and vapours in dry octan-1-ol at 298 K.

Ostwald solubility coefficients of 74 compounds in dry octan-1-ol at 298 K have been determined, and have been combined with literature values and additional values we have calculated from solubilities in dry octan-1-ol and vapour pressures to yield a total of 161 log L(OctOH) values at 298 K. These L(OctOH) values are identical to gas-to-dry octan-1-ol partition coefficients, often denoted as K(OA). Application of the solvation equation of Abraham to 124 values as a training set yielded a correlation equation with n = 124, S.D. = 0.125, r2 = 0.9970 and F = 7731. This equation was then used to predict 32 values of log L(OctOH) as a test set, giving a standard deviation, S.D. of 0.131, an average absolute deviation of 0.085 and an average deviation of -0.009 log units. The solvation equation for the combined 156 log L(OctOH) values was log L(OctOH) = -0.120 - 0.203R2 + 0.560pi2(H) + 3.560 sum(alpha2(H)) + 0.702 sum(beta2(H)) + 0.939 logL16, n =156, r2 = 0.9972, S.D. = 0.125, F = 10573, where, n is the number of data points (solutes), r the correlation coefficient, S.D. the standard deviation and F is the F-statistic. The independent variables are solute descriptors as follows: R2 is an excess molar refraction, pi2(H) the dipolarity/polarisability, sum(alpha2(H)) the overall or summation hydrogen-bond acidity, sum(beta2(H)) the overall or summation hydrogen-bond basicity and L16 is the Ostwald solubility coefficient on hexadecane at 298 K. The equation is consistent with similar equations for the solubility of gases and vapours into methanol, ethanol and propan-1-ol. It is suggested that the equation can be used to predict further values of log L(OctOH), for which the solute descriptors are known, to within 0.13 log units.

SOLUBILITY OF GASES AND VAPOURS IN PROPAN-1-OL AT 298 K

Literature values of the Ostwald solubility coefficient of gases and vapours in propan-1-ol at 298u2005K were combined with additional values calculated from solubilities in propan-1-ol and vapour pressures to yield a total of 79 log LPrOH values at 298u2005K. Seventy-seven of these values were correlated through the general solvation equation to give the regression n n nlog LPrOH = -0.028 - 0.185R2 + 0.648π2H + 4.022Σα2H + 1.043Σβ2H + 0.869log L16 n n n n nn = 77, r2 = 0.9976, SD = 0.12, F = 6073 n n n nA correlation equation was also constructed for the transfer of solutes from water to propan-1-ol. Both equations suggest that propan-1-ol as a solvent is less dipolar, more acidic and less basic than methanol or ethanol, but the differences between the three alcohols are very small. Comparison with equations for transfer to wet alcohols shows that the addition of water to alcohols has little effect on their dipolarity/polarizability or hydrogen bond basicity, but considerably increases the hydrogen bond acidity. The wet alcohols are more hydrophilic (less hydrophobic) than the dry alcohols. Copyright

Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP-K2) as an antiinflammatory target: discovery and in vivo activity of selective pyrazolo[1,5-a]pyrimidine inhibitors using a focused library and structure-based optimization approach.

A novel class of mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP-K2) inhibitors was discovered through screening a kinase-focused library. A homology model of MAPKAP-K2 was generated and used to guide the initial SAR studies and to rationalize the observed selectivity over CDK2. An X-ray crystal structure of a compound from the active series bound to crystalline MAPKAP-K2 confirmed the predicted binding mode. This has enabled the discovery of a series of pyrazolo[1,5-a]pyrimidine derivatives showing good in vitro cellular potency as anti-TNF-α agents and in vivo efficacy in a mouse model of endotoxin shock.