Abstract

The mechanism by which human alpha-1-acid glycoprotein (hAAG) decreases the intrinsic clearance of prazosin was investigated in primary rat hepatocyte cultures. The intrinsic clearance, equal to the ratio of rate of drug elimination to unbound concentration, is the composite result of uptake and metabolism. From separate elimination and uptake studies we found that the ability of hAAG to decrease the intrinsic clearance of prazosin was related to decreased uptake and not to changes in metabolism. In order to identify the underlying mechanism for the observed decrease in uptake the effect of bovine alpha-1-acid glycoprotein (AAG) on prazosin intrinsic clearance and uptake was also determined. Bovine AAG, in contrast to hAAG, had neither a statistical significant effect on prazosin uptake nor on prazosin intrinsic clearance. Based upon the fact that bovine AAG has little or no ability to bind prazosin in contrast to hAAG, we hypothesize that when a AAG, capable of binding prazosin, associated with cell membranes it will retard the diffusion of drug through the cellular stagnant diffusion layer. Human serum albumin (HSA), in contrast to hAAG, did not decrease the uptake of prazosin although HSA binds prazosin and associates with hepatocytes to the same degree as hAAG. However, HSA associated with rat hepatocytes, in contrast to hAAG, appears to have an operationally reduced ability to bind prazosin suggesting that HSA may not be able to retard diffusion of prazosin to the same degree as hAAG. HSA also may release prazosin which subsequently serves to increase the active concentration of prazosin at the cell surface.