Prediction of V_ss from In Vitro Tissue-Binding Studies

Abstract

ABSTRACT:To predict volume of distribution at steady-state (V ss ), empirical (e.g., allometry) and mechanistic (using physicochemical property data and plasma protein binding) methods have been used. None of these approaches has been able to predict V ss accurately for the total compliment of a wide range of drugs. Therefore, alternative approaches would be of value. This study evaluates the utility of in vitro nonspecific tissue-binding measurements in predicting V ss for a wide range of drugs in rats. Literature as well as proprietary compounds were studied. It was found that in vitro tissue-binding measurements combined with calculated effects of the pH partition hypothesis often predict V ss more accurately than other available mechanistic methods and that this approach can compliment existing methods. The V ss values for some compounds were not accurately predicted using either nonspecific tissue-binding experiments or other available mechanistic methods. The V ss for these drugs may not be describable by nonspecific tissue binding alone; there may be significant specific components to the mechanism of distribution for these drugs, such as pH-dependent uptake into lysosomes (primarily strongly basic drugs), active transport, and/or enterohepatic recirculation. A lack of prediction for certain drugs warrants further investigation into these mechanisms and their application to more accurate prediction of V ss by mechanistic means.The apparent volume of distribution at steady state (V ss ) is one of the primary descriptive terms derived from pharmacokinetic (PK) analysis of the concentration-time profile after intravenous administration of drugs.

Predicting volume of distribution with decision tree-based regression methods using predicted tissue:plasma partition coefficients

“…However, here we used data for rat K t:p , rather than human K t:p , when building models predicting log K t:p . As mentioned earlier, this was due to the availability of more rat K t:p data than human K t:p data in the literature, but clearly there are species differences that lead to different values of K t:p for rats and humans [6,39]. In addition, even when using rat K t:p data, the number of compounds with known log K t:p value available for some tissues (i.e.…”

“…Although this apparent Vss has no physiological meaning, its estimation is important because it predicts the drug’s plasma concentration for a given amount of drug in the body and it influences the drug’s half-life [2,3], which in turn is very important to determine the correct dosage regimen that clinicians should prescribe to patients [4,5]. Hence, one needs to estimate or predict Vss using an in vivo , in vitro or in silico approach [6-9]. …”

Drug Discovery Methods for Studying Brain Drug Delivery and Distribution

“…For instance, it has been documented that predictions of the pharmacokinetic parameter apparent volume of distribution at steady state (V ss ) for 36 compounds, based on measurement of the unbound drug fraction in 15 different tissues, were less accurate for acidic and strongly basic substances (Berry et al 2010). However, after making allowance for the ionic effects of tissue-to-blood pH gradients, the predictions for V ss were accurate within a threefold range for 81 % of the compounds studied.…”

The Øie–Tozer model of drug distribution and its suitability for drugs with different pharmacokinetic behavior

“…Alternatively, this analysis can be performed using limited set of parameters, such as drug distribution to selected tissues [4,11], in vitro drug-tissue binding [12,13], drug interaction with artificial membranes [14] and so on. Volume of distribution of a specific drug can be also predicted based on its PK data in other species (allometric scaling) and taking into account parameters that describe drug's molecular properties (molecular descriptors) [15,16].…”