Pharmacokinetic studies of Gln117 tissue-type plasminogen activator in rats.

Abstract

Gln117 t-PA is a mutant type of tissue-type plasminogen activator (mt-PA), which is generated by the removal of a high mannose oligosaccharide resulting from the mutation of amino acid #117, from asparagine (Asn) to glutamine (Gln). The plasma concentration, distribution, metabolism and excretion of Gln117 t-PA were investigated after a single intravenous administration of 125I-Gln117 t-PA or Gln117 t-PA, comparing with wild-type t-PA (WT t-PA). The plasma concentration of Gln117 t-PA decreased more slowly than that of WT t-PA, plasma clearance (CL(p)), and that of Gln117 t-PA in rats was approximately 2.6 times lower than that of WT t-PA. The highest radioactivity was found in the liver at 5 min after intravenous administration of [125I]Gln117 t-PA to rats, but the radioactivity in the liver was lower than that after intravenous administration of [125I]WT t-PA in our previous paper. Within 288 h after intravenous administration of [125I]Gln117 t-PA to rats, 88.5 and 5.5% of administered radioactivity were excreted into urine and feces, respectively. In a gel-filtration chomatographic (GFC) analysis of plasma, Gln117 t-PA formed complexes with plasma proteins, similarly to WT t-PA. The hepatic clearance (CL(hep)) of both t-PAs was evaluated by comparing the plasma concentration after a constant intravenous infusion with that after a constant intraportal venous infusion. The CL(hep) of Gln117 t-PA was 6.5 times lower than that of WT t-PA. These results indicate that the low uptake of Gln117 t-PA to the liver reduces CL(p) compared with WT t-PA.