Rat PermQ: A permeability- and perfusion-based physiologically based pharmacokinetic model for improved prediction of drug concentration-time profiles in rat.

Abstract

A new rat permeability- and perfusion-limited physiologically based pharmacokinetic model, "rat PermQ," was developed with the goal of improving concentration-time (C-t) predictions of drugs. Similar to the previously published human PermQ, drugs can reversibly distribute between capillaries and interstitial fluid by fenestra or discontinuities in capillaries or by transcellular diffusion through endothelial cells. Drugs also can be partitioned into intracellular phospholipids and neutral lipids in the cytosol. For acidic drugs, active uptake transport and an empirical protein binding correction factor were considered. A shallow distribution compartment was added for basic drugs to account for early distribution. In vitro and in vivo experimental inputs were collected in-house or from the literature. C-t profiles were predicted for 7 drugs (2 acidic, 2 neutral, and 3 basic) with 3 models: Rodgers and Rowland (RR), a perfusion-limited membrane-based model, and rat PermQ. Results indicate the importance of consistent, species-specific in vitro inputs. In general, rat PermQ predicted C-t profiles at least as well as the other models. For acidic drugs, rat PermQ predictions improved with incorporation of uptake transport and the empirical protein binding factor. For neutral drugs, RR predicted digoxin C-t profiles better compared with rat PermQ, while midazolam predictions with rat PermQ were improved with the use of in-house in vitro experimental inputs. Rat PermQ predicted C-t profiles for all 3 bases better than RR and perfusion-limited membrane-based model, and addition of a shallow compartment greatly improved the predictions. Rat and human PermQ allowed several hypotheses to be simulated for putative uptake mechanisms for atenolol and glyburide. SIGNIFICANCE STATEMENT: A new physiologically based pharmacokinetic framework, rat PermQ, was developed. This model predicted plasma concentration-time profiles of the tested drugs as well as or better than published physiologically based pharmacokinetic models. PermQ allowed several hypotheses to be simulated for uptake mechanisms in rats and humans. The work highlights the importance of accurate in vitro parameters such as drug plasma protein binding and blood-to-plasma ratio. The model can aid in testing new hypotheses to explain poorly understood observations in distribution and elimination of drugs.