Interdependent effect of P-glycoprotein-mediated drug efflux and intracellular drug binding on intracellular paclitaxel pharmacokinetics: application of computational modeling.

Abstract

Intracellular concentration of paclitaxel is determined by the extracellular drug concentration, the level of the mdr1 P-glycoprotein (Pgp), and binding to intracellular proteins including tubulins/microtubules. The present study used a computational method to examine the effects of these factors, singly and in combination, on intracellular paclitaxel pharmacokinetics. The study was performed using our previously described intracellular pharmacokinetic model. The parameters representing Pgp-mediated drug efflux and intracellular drug binding (i.e., number of Pgp and binding sites and binding affinity) were altered systematically and used to generate computer simulations depicting the intracellular paclitaxel pharmacokinetics at clinically relevant extracellular (e.g., plasma) drug concentrations. The simulation results indicate that all four factors played a role in determining the intracellular drug accumulation. The rank order of the importance of these parameters was extracellular drug concentration >> intracellular binding capacity > intracellular binding affinity > Pgp expression. The results further showed that omission of one or more of these factors in the experimental design would lead to erroneous conclusions on the importance of other factors, as simultaneous changes in more than one parameter altered the relative importance and offset the effects of other parameters. In summary, results of the present study demonstrate the use of computational modeling to depict the effects of biological parameters such as drug efflux transporters, drug binding sites, and binding affinity on intracellular accumulation and retention of drugs that bind to cellular components.