Received for publication September 5, 2006.
Revised December 14, 2006.
Accepted for publication December 15, 2006.

Characterization of the hepatic disposition of lanoteplase, a rationally designed variant of tissue plasminogen activator, in rodents

Abstract

Lanoteplase is a recombinant mutant of tissue-type plasminogen activator (t-PA) that was developed with an aim to overcome the drawback of rapid systemic elimination of t-PA. In this study, we examined the disposition profile of lanoteplase in vivo and the kinetics of receptor-mediated endocytosis (RME) of this recombinant t-PA in vitro in order to kinetically characterize the mechanism(s) underlying its tissue distribution and elimination. Integration plot analysis of the initial-phase tissue distribution in rats revealed a much lower uptake clearance (CL_uptake) of lanoteplase in the liver than that of t-PA. Rate constants for cell-surface binding, internalization and degradation of lanoteplase were also lower than those for t-PA in primary cultured rat hepatocytes. These results suggest that the improved stability of lanoteplase in vivo could be accounted for by the delay in the RME of this recombinant protein. The CL_uptake in the liver decreased with co-administration of lactoferrin, a ligand for the low-density lipoprotein receptor-related protein (LRP) and the asialoglycoprotein (ASGP) receptors in normal mice, and in lrpap1^(-/-) mice, which have a hereditary deficiency of LRP; In contrast, CL_uptake was not affected by mannose, whereas that of t-PA decreased with both ligands and in the lrpap1^(-/-) mice. Thus, the hepatic disposition of lanoteplase appears to be mediated by common specific receptors for t-PA, including LRP and the ASGP receptors, whereas the mannose receptor appears to be only minimally involved in the disposition of lanoteplase.

Key words: cytokines, drug clearance, drug disposition, hepatic uptake, pharmacokinetics