Yes / A simple method is reported for the estimation of in vivo air-tissue partition coefficients of VOCs and of in vitro blood-tissue partition coefficients for volatile organic compounds and other compounds. Linear free energy relationships for tissues such as brain, muscle, liver, lung, kidney, heart, skin and fat are available and once the Abraham descriptors are known for a compound, no more than simple arithmetic is required to estimate air-tissue and blood-tissue partitions.

Yes / BACKGROUND: There is considerable interest in the blood–tissue distribution of agrochemicals, and a number of researchershave developed experimental methods for in vitro distribution. These methods involve the determination of saline–blood andsaline–tissue partitions; not only are they indirect, but they do not yield the required in vivo distribution.RESULTS: The authors set out equations for gas–tissue and blood–tissue distribution, for partition from water into skin andfor permeation from water through human skin. Together with Abraham descriptors for the agrochemicals, these equationscan be used to predict values for all of these processes. The present predictions compare favourably with experimental in vivoblood–tissue distribution where available. The predictions require no more than simple arithmetic.CONCLUSIONS: The present method represents a much easier and much more economic way of estimating blood–tissuepartitions than the method that uses saline–blood and saline–tissue partitions. It has the added advantages of yielding therequired in vivo partitions and being easily extended to the prediction of partition of agrochemicals from water into skin andpermeation from water through skin.

Physiologically based pharmacokinetic (PBPK) modeling is a tool used in drug discovery and human health risk assessment. PBPK models are mathematical representations of the anatomy, physiology and biochemistry of an organism. PBPK models, using both compound and physiologic inputs, are used to predict a drug’s pharmacokinetics in various situations. Tissue to plasma partition coefficients (Kp), a key PBPK model input, define the steady state concentration differential between the tissue and plasma and are used to predict the volume of distribution. Experimental determination of these parameters once limited the development of PBPK models however in silico prediction methods were introduced to overcome this issue. The developed algorithms vary in input parameters and prediction accuracy and none are considered standard, warranting further research. Chapter 2 presents a newly developed Kp prediction algorithm that requires only readily available input parameters. Using a test dataset, this Kp prediction algorithm demonstrated good prediction accuracy and greater prediction accuracy than preexisting algorithms. Chapter 3 introduced a decision tree based Kp prediction method. In this novel approach, six previously published algorithms, including the one developed in Chapter 2, were utilized. The aim of the developed classifier was to identify the most accurate tissue-specific Kp prediction algorithm for a new drug. A dataset consisting of 122 drugs was used to train the classifier and identify the most accurate Kp prediction algorithm for a certain physico-chemical space. Three versions of tissue specific classifiers were developed and were dependent on the necessary inputs. The use of the classifier resulted in a better prediction accuracy as compared to the use of any single Kp prediction algorithm for all tissues; the current mode of use in PBPK model building. With built-in estimation equations for those input parameters not necessarily available, this Kp prediction tool will provide Kp prediction when only limited input parameters are available. The two presented innovative methods will improve tissue distribution prediction accuracy thus enhancing the confidence in PBPK modeling outputs.

Physiologically based pharmacokinetic (PBPK) modeling is a tool used in drug discovery and human health risk assessment. PBPK models are mathematical representations of the anatomy, physiology and biochemistry of an organism. PBPK models, using both compound and physiologic inputs, are used to predict a drug’s pharmacokinetics in various situations. Tissue to plasma partition coefficients (Kp), a key PBPK model input, define the steady state concentration differential between the tissue and plasma and are used to predict the volume of distribution. Experimental determination of these parameters once limited the development of PBPK models however in silico prediction methods were introduced to overcome this issue. The developed algorithms vary in input parameters and prediction accuracy and none are considered standard, warranting further research. Chapter 2 presents a newly developed Kp prediction algorithm that requires only readily available input parameters. Using a test dataset, this Kp prediction algorithm demonstrated good prediction accuracy and greater prediction accuracy than preexisting algorithms. Chapter 3 introduced a decision tree based Kp prediction method. In this novel approach, six previously published algorithms, including the one developed in Chapter 2, were utilized. The aim of the developed classifier was to identify the most accurate tissue-specific Kp prediction algorithm for a new drug. A dataset consisting of 122 drugs was used to train the classifier and identify the most accurate Kp prediction algorithm for a certain physico-chemical space. Three versions of tissue specific classifiers were developed and were dependent on the necessary inputs. The use of the classifier resulted in a better prediction accuracy as compared to the use of any single Kp prediction algorithm for all tissues; the current mode of use in PBPK model building. With built-in estimation equations for those input parameters not necessarily available, this Kp prediction tool will provide Kp prediction when only limited input parameters are available. The two presented innovative methods will improve tissue distribution prediction accuracy thus enhancing the confidence in PBPK modeling outputs.