No abstract

The permeability of biological membranes is one of the most important determinants of the pharmacokinetic processes of a drug. Although it is often accepted that many drug substances are transported across biological membranes by passive transcellular diffusion, a recent hypothesis speculated that carrier-mediated mechanisms might account for the majority of membrane drug transport processes in biological systems. Based on evidence of the physicochemical characteristics and of in vitro and in vivo findings for marketed drugs, as well as results from real-life discovery and development projects, we present the view that both passive transcellular processes and carrier-mediated processes coexist and contribute to drug transport activities across biological membranes.

ABSTRACT:The use of in vitro data for quantitative predictions of transportermediated elimination in vivo requires an accurate estimation of the transporter Michaelis-Menten parameters, V max and K m , as a first step. Therefore, the experimental conditions of in vitro studies used to assess hepatic uptake transport were optimized regarding active transport processes, nonspecific binding, and passive diffusion (P dif ). A mechanistic model was developed to analyze and accurately describe these active and passive processes. This twocompartmental model was parameterized to account for nonspecific binding, bidirectional passive diffusion, and active uptake processes based on the physiology of the cells. The model was used to estimate kinetic parameters of in vitro transport data from organic anion-transporting peptide model substrates (e.g., cholecystokinin octapeptide deltorphin II, fexofenadine, and pitavastatin). Data analysis by this mechanistic model significantly improved the accuracy and precision in all derived parameters [mean coefficient of variations (CVs) for V max and K m were 19 and 23%, respectively] compared with the conventional kinetic method of transport data analysis (mean CVs were 58 and 115%, respectively, using this method). Furthermore, permeability was found to be highly temperature-dependent in Chinese hamster ovary (CHO) control cells and artificial membranes (parallel artificial membrane permeability assay). Whereas for some compounds (taurocholate, estrone-3-sulfate, and propranolol) the effect was moderate (1.5-6-fold higher permeability at 37°C compared with that at 4°C), for fexofenadine a 16-fold higher passive permeability was seen at 37°C. Therefore, P dif was better predicted if it was evaluated under the same experimental conditions as V max and K m , i.e., in a single incubation of CHO overexpressed cells or rat hepatocytes at 37°C, instead of a parallel control evaluation at 4°C.

No abstract

No abstract