Abstract

The use of in vitro data to predict the pharmacokinetics (PK) of drugs whose disposition is mediated by transporters is complicated due to unknown transporter expression levels in individual tissues both in vivo as well as in various in vitro cell culture systems. The contribution of passive diffusion to drug transfer between extracellular and intracellular space  in individual tissues is  another important aspect to  consider for drugs with low permeability and slow diffusion through cellular membranes. The permeability-surface area product (PStc) is commonly used to describe the rate of passive diffusion through membranes. Estimation of PStc values for  different tissues incorporated in PBPK models is not well-established due to unknown physiological aspects of individual tissues, e.g., cell surface areas. We propose a new method for describing the passive diffusion in different tissues by scaling the PStc values to tissue cell volumes. The method was further extended to estimate  the contribution of passive and carrier-mediated transport in  vivo  from in  vitro  measurements. Valsartan was used as a model compound with distribution and clearance dependent on transporter activity. GastroPlus™ 7.0  with its PBPKPlus™ Module (Simulations Plus, Inc., Lancaster, CA) was used to simulate plasma concentration- time (Cp-time) profiles utilizing physiologically based pharmacokinetic (PBPK)  models based on both  animal and human based on in silico and in vitro parameters. This method is a promising tool for prediction of the pharmacokinetics of drugs whose disposition cannot be described by well-stirred tissue models, and it expands the predictive capabilities of PBPK modeling approaches for prediction of pharmacokinetics based on in vitro  data to a wider range of compounds.

17th North American ISSX Meeting, October 16-20, 2011, Atlanta, GA

By Viera Lukacova, Michael B. Bolger, Walter S. Woltosz, Neil J. Parrott, Agnès Poirier and T. Lavè