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 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.
Footnotes
-
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
-
doi:10.1124/dmd.106.012518.
-
ABBREVIATIONS: t-PA, tissue-type plasminogen activator; RME, receptor-mediated endocytosis; LRP, low-density lipoprotein receptor-related protein; ASGP, asialoglycoprotein; PAI, plasminogen activator inhibitor; TCA, trichloroacetic acid; CLtot, total body clearance; CLuptake, tissue uptake clearance; Cp, plasma concentration; AUC, area under the plasma concentration-time curve; Kp, tissue/plasma concentration ratio; MES, 2-(N-morpholino)ethanesulfonic acid; LRPAP, low-density lipoprotein receptor-related protein-associated protein.
- Received September 3, 2006.
- Accepted December 15, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|