A Priori Prediction of Tissue:Plasma Partition Coefficients of Drugs to Facilitate the Use of Physiologically‐Based Pharmacokinetic Models in Drug Discovery

Plasma vs heart tissue concentration in humans – literature data analysis of drugs distribution

“…The distribution of a drug among tissues is characterized by the Kp value which is defined as the ratio of the total concentration of compound in the tissue to the total concentration of compound in the plasma at steady state [4]. Although there are approaches to estimate a priori the steady-state Kp values, the measured tissue data remain of the greatest value [4][5][6][7]. There are studies reporting the correlation between tissue-to-blood partition coefficients in rats obtained in vitro and in vivo.…”

Physiologically based pharmacokinetic modelling: a sub-compartmentalized model of tissue distribution

“…The choice of sub-compartments is motivated by the availability of physiological data and for pharmacokinetic and pharmacodynamic reasons (11,19,20). For the generic parameterization, drug exchange by passive diffusion, non-saturable distribution processes and the absence of metabolic processes is assumed, as in existing models for predicting tissue partition coefficients (12)(13)(14)16). Extensions are discussed.…”

“…To recognize this and to find appropriate experimental realizations was the break-through in a priori determination of partition coefficients (13,14). The differences between existing tissue distribution models regard (i) the tissue constituents that are taken into account and (ii) the approximation of partition coefficients for the resulting constituents by in vitro data.…”

“…Parameter values can be found in (16,26) for the species rat. In their seminal papers in 2000/01 (13,14), Poulin and Theil proposed an in silico approach to a priori predict tissue-plasma partition coefficients solely based on few compound specific in vitro data. They assumed that the compound is present in dissolved form in tissue water, that it may bind to macromolecules in the interstitial space, and distribute into neutral lipids or phospholipids in the cellular space, while other effects are considered negligible.…”

“…The experimental determination of tissue affinities can be costly and time consuming, and requires a substantial amount of compound, which is rarely available during discovery and early candidate selection (12). As a solution to this problem Poulin and Theil proposed in their seminal papers (13,14) to a priori predict the tissue distribution of a drug based on mechanistic description of the underlying physiology and the properties of drugs. Their key idea is to regard the most important tissue constituents-like water, neutral lipids, phospholipids, macro-molecules-and to predict the overall tissue distribution by means of the distribution into these tissue constituents.…”