RT Journal Article SR Electronic T1 Characterization of the Hepatic Disposition of Lanoteplase, a Rationally Designed Variant of Tissue Plasminogen Activator in Rodents JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 469 OP 475 DO 10.1124/dmd.106.012518 VO 35 IS 3 A1 Kazumi Komoriya A1 Yukio Kato A1 Yujiro Hayashi A1 Kazuhiro Ohsuye A1 Ryuichiro Nishigaki A1 Yuichi Sugiyama YR 2007 UL http://dmd.aspetjournals.org/content/35/3/469.abstract AB 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 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 (CLuptake) 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 CLuptake in the liver decreased with coadministration 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, CLuptake 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 seems to be mediated by common specific receptors for t-PA, including LRP and the ASGP receptors, whereas the mannose receptor seems to be only minimally involved in the disposition of lanoteplase. The American Society for Pharmacology and Experimental Therapeutics