Development of quantitative structure-pharmacokinetic relationships.

Abstract

Quantitative structure-activity relationships (QSAR) relating biological activity to physiochemical descriptors have been successfully used for a number of years. It is also long recognized that pharmacokinetic parameters may play an important and even determinant role in drug action. This prompted several researchers to focus attention to pharmacokinetic parameters as potential descriptors in quantitative drug design. A number of examples of quantitative structure-pharmacokinetic relationships (QSPR) have appeared in the literature. The present contribution reviews some developments in this field. In particular, a number of concepts and problems are critically discussed, rather than compilations of examples already published in recent reviews. Attention will be paid to the main processes of the pharmacokinetic or toxicokinetic phase in drug action, including absorption, distribution and elimination (biotransformation and excretion). It is clear that quantitative approaches are of considerable interest to toxicologists, since these methods may contribute to the development of real predictive toxicology.

The influence of conformational factors on the metabolic conjugation of aryloxyacetates

“…In contrast, the discernment of the relationships between structure and various aspects of absorption, distribution, metabolism and excretion has proved more elusive (for reviews see Hansch 1972;Seydel & Schaper 1982;Mayer & van de Waterbeemd 1985; and a study by Ong et a1 1982). Absorption, distribution and excretion generally involve passive diffusion, hence it is no wonder that these processes are related to lipophilicity.…”

Quantitative Structure–Pharmacokinetic/Pharmacodynamic Relationships of Corticosteroids in Man

“…The final PK parameter of interest was the percent of oral absorption ( F ). Again, while traditional studies have focused on log P values,2,3 drugs that are absorbed by passive processes can be readily characterized by the polar molecular surface area 26. This approach is not confined to a congeneric series, and recent studies continue to confirm this relationship 48,49.…”

“…The primary goal of quantitative structure–activity/pharmacokinetic relationships (QSAR/QSPKR) modeling is to develop mathematical expressions correlating activity and pharmacokinetic (PK) parameters to physicochemical properties of a congeneric series of compounds 1–4. Since the ground‐breaking work of Hansch and colleagues,5 the QSAR approach has been used to predict the optimum molecular structure of drugs and to provide an additional means by which to study and understand their mechanisms of action.…”

Molecular Determinants Responsible for Sedative and Non-sedative Properties of Histamine H1–Receptor Antagonists

“…Quantitative analyses of the chemical structures of compounds can be useful to explain and predict their effects on physiological functions (11): many studies on quantitative structure-activity relationships (QSAR) have been successful in the analyses and prediction of pharmacological effects (12), enzymatic activities (13), affinities for receptor proteins (14), pharmacokinetic parameters (15), and drug metabolism (16). However, there is no report concerning a QSAR model specifically designated for the membrane-penetrating ability of antihistamines; therefore, we tried to establish a QSAR model to explain and predict membrane-penetrating ability of antihistamines for their sedative and non-sedative properties on the basis of our previous report (10).…”