Yuan H. Zhao

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. 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.

Correlation and prediction of a large blood-brain distribution data set: an LFER study

We report linear free energy relation (LFER) models of the equilibrium distribution of molecules between blood and brain, as log BB values. This method relates log BB values to fundamental molecular properties, such as hydrogen bonding capability, polarity/polarisability and size. Our best model of this form covers 148 compounds, the largest set of log BB data yet used in such a model, resulting in R(2)=0.745 and e.s.d.=0.343 after inclusion of an indicator variable for carboxylic acids. This represents rather better accuracy than a number of previously reported models based on subsets of our data. The model also reveals the factors that affect log BB: molecular size and dispersion effects increase brain uptake, while polarity/polarisability and hydrogen-bond acidity and basicity decrease it. By splitting the full data set into several randomly selected training and test sets, we conclude that such a model can predict log BB values with an accuracy of less than 0.35 log units. The method is very rapid-log BB can be calculated from structure at a rate of 700 molecules per minute on a silicon graphics O(2).

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.

Interspecies correlations of toxicity to eight aquatic organisms: Theoretical considerations

Interspecies correlations allow the prediction of toxicity to a number of other species. However, little attention has been paid to the theoretical considerations of the interspecies relationship based on the differences of bio-uptake and toxic mechanism between species. This study examines the interspecies correlations of toxicity between species of Vibrio fischeri, river bacteria, algae, Daphnia magna, carp, Tetrahymena pyriformis, fathead minnow and guppy based on the theoretical background. The results show that there are good interspecies correlations between marine bacterium and fresh water bacteria or fish and fish. It is suggested that compounds share the same bio-uptake and toxic mechanism of action between the species. On the other hand, poor interspecies relationships were found between toxicities to algae and T. pyriformis or D. magna. It is suggested that compounds have different toxic mechanisms of action between these species. Interspecies relationships can be improved by inclusion of the octanol/water partition coefficient or the energy of the lowest unoccupied molecular orbital. They reflect the difference of bio-uptake or toxic mechanism of action between species for organic compounds. Benzoic acids show very different toxicity contributions to the three species, V. fischeri, D. magna and carp. They can be easily absorbed into the unicellular bacteria, V. fischeri. On the contrary, the skin and lipid content of multicellular organisms, such as D. magna and fish, can strongly inhibit the bio-uptake for ionizable compounds, which results in the different toxic effect between V. fischeri and D. magna or carp. Good correlation coefficients were observed between toxicities to V. fischeri and D. magna or fishes by inclusion of hydrophobic and ionization parameters. V. fischeri or D. magna can serve as a surrogate of fish toxicity for hydrophobic and ionizable compounds studied. Toxic mechanisms of action are discussed based on the theoretical background of the interspecies correlation.

Characterisation of the water/o-nitrophenyl octyl ether system in terms of the partition of nonelectrolytes and of ions

The Abraham linear free energy relationship, or solvation equation, has been applied to literature data on the partition of nonelectrolytes in the water to o-nitrophenyl octyl ether (NPOE) system. The resulting equation is compared to equations for other water to solvent systems using the D-parameter of Abraham and Martins and the theta-parameter of Ishihama and Asakawa. It is shown that as a solvent in partitioning systems, NPOE quite resembles nitrobenzene and 1,2-dichloroethane, and that the latter does not resemble an alkane-like solvent. Using descriptors for simple ions that we have previously obtained, we show that ions and nonelectrolytes can be included in the same linear free energy relationship.

Linear and non-linear relationships between soil sorption and hydrophobicity: model, validation and influencing factors.

The hydrophobic parameter represented by the octanol/water partition coefficient (logP) is commonly used to predict the soil sorption coefficient (K(oc)). However, a simple non-linear relationship between logK(oc) and logP has not been reported in the literature. In the present paper, soil sorption data for 701 compounds was investigated. The results show that logK(oc) is linearly related to logP for compounds with logP in the range of 0.5-7.5 and non-linearly related to logP for the compounds in a wide range of logP. A non-linear model has been developed between logK(oc) and logP for a wide range of compounds in the training set. This model was validated in terms of average error (AE), average absolute error (AAE) and root-mean squared error (RMSE) by using an external test set with 107 compounds. Nearly the same predictive capacity was observed in comparison with existing models. However, this non-linear model is simple, and uses only one parameter. The best model developed in this paper is a non-linear model with six correction factors for six specific classes of compounds. This model can well predict logK(oc) for 701 diverse compounds with AAE = 0.37. The reasons for systemic deviations in these groups may be attributed to the difference of sorption mechanism for hydrophilic/polar compounds, low solubility for highly hydrophobic compounds, hydrolysis of esters in solution, volatilization for volatile compounds and highly experimental errors for compounds with extremely high or low sorption coefficients.

Toxicity of organic chemicals to Tetrahymena pyriformis: effect of polarity and ionization on toxicity.

A large toxicity data set containing the toxicities of 250 phenols and 252 aliphatic compounds to Tetrahymena pyriformis was classified into different groups based on the structure and substituted functional groups. QSAR analysis was performed between the toxicity and calculated descriptors, expressed as hydrophobicity, polarity and ionization. Through an analysis of these class-based compounds, significant relationships were developed between the toxicity and hydrophobicity for non-polar and polar narcotic compounds. A single model for both non-polar and polar narcotics was developed by inclusion of a polar descriptor as well as the hydrophobic parameter logP. The highly hydrophobic polar narcotics can be treated as non-polar narcotics because their polar functional group(s) makes a relatively small contribution as compared to their hydrophobicity. A cut-off to classify the polar narcotics is difficult because polarity of a chemical not only depends on one or two functional groups (i.e. amino- or hydroxyl-) substituted on the compound, but also on the overall hydrophobicity of the compound. The toxicity increases with increasing the ionization by increasing the interaction between ionisable compounds and macromolecules at the target sites. However, the toxicity decreases with increasing the ionization by decreasing the bio-uptake for extremely ionisable compounds. A significant QSAR equation has been developed between the toxicity to T. pyriformis and the descriptors of hydrophobic, polarity/polarizability and ionization parameters for 457 compounds (R(2)=0.87). These compounds contain non-polar, polar and reactive compounds, and some of them are extremely ionisable. The models developed are simple, interpretable and transparent, using a small number of descriptors.

Toxicity of organic pollutants to seven aquatic organisms: effect of polarity and ionization

The toxicity of organic chemicals to Vibrio fischeri, river bacteria, algae, Daphnia magna and fishes were analysed. The results showed that the toxicity of chemicals to narcotics was dependent on hydrophobicity. A single model for both polar and non-polar narcotics was developed by inclusion of a polarity descriptor as well as the hydrophobic parameter. The highly hydrophobic polar narcotics could be treated as non-polar narcotics because their polar functional group(s) make(s) a relatively small contribution to polarity as compared with their hydrophobicity. In order to investigate the toxic mechanism of action for reactive compounds, the response–surface approach was used to develop models derived from easily calculated descriptors. The stepwise analysis selected the octanol/water partition coefficient and a polarity descriptor to parameterize bio-uptake and reactivity, respectively, for seven species. Benzoic acids can be easily absorbed into the unicellular bacteria, but this is not the case for multicellular D. magna and fish. Their toxicity to V. fischeri is much higher than that to D. magna and carp. Regression analysis was performed based on the model that we developed for ionizable compounds. Good correlations were observed by introducing the correction factor for ionizable compounds. The toxic mechanisms are discussed.