Application of a convective-dispersion model to predict in vivo hepatic clearance from in vitro measurements utilizing cryopreserved human hepatocytes.

Growing interest in the prediction of in vivo pharmacokinetic data from purely in vitro data has grown into a process known as the in vitro-in vivo correlation (IVIC). IVIC can be used to determine the viability of new chemical entities in the early drug development phases, leading to a reduction of resource spending by many large pharmaceutical companies. Here, a convective-dispersion model was developed to predict the total hepatic clearance of six drugs using pharmacokinetic data obtained from in vitro metabolism studies in which the drug disappearance from suspensions of human cryopreserved hepatocytes was measured. Predicted in vivo hepatic clearances estimated by the convective-dispersion model were ultimately compared to the actual clearance values and to in vivo hepatic clearances that were scaled based on the well-stirred model. Finally, sensitivity studies were performed to determine the dependence of hepatic clearance on a number of physiological model parameters. Results reaffirmed that low clearance drugs exhibit rate-limited metabolism, and their hepatic clearances are thus independent of blood flow characteristics, whereas drugs with relatively higher clearance values show a more pronounced dependence on the flood flow properties of dispersion and convection. Absent a priori knowledge about the flow-dependent properties of a drug's clearance, the convective dispersion model applied to disappearance data acquired from cryopreserved human hepatocytes is likely to provide satisfactory estimates of hepatic drug clearance.

Oxygen and inulin transport measurements in a planar tissue-engineered bioartificial organ.

In vivo oxygen and inulin transport rates were measured in a planar tissue-engineered bioartificial organ implanted in a rat. A compartmental model was used to describe the transport of oxygen and inulin between the cell chamber, across the immunoisolation membrane, and within the neovascularized region adjacent to the immunoisolation membrane. A nonlinear regression analysis of the plasma inulin levels and the oxygen transport rate into the device provided information on the degree of vascularization in the region adjacent to the bioartificial organ. Key parameters that were obtained from the analysis of the in vivo transport data included the average capillary blood oxygen partial pressure, the Krogh tissue cylinder radius, the extracellular volume fraction, and the capillary blood residence time. These four parameters are important indicators for assessing the degree of vascularization in the tissue adjacent to the immunoisolation membrane in the bioartificial organ. The oxygen and inulin transport technique reported here is a useful tool for describing the in vivo transport characteristics of a bioartificial organ and for assessment of the vascularization within tissue engineered structures.