Pharmacokinetic properties of an Escherichia-coli-produced recombinant plasminogen activator (BM 06.022) in rabbits.
The recombinant plasminogen activator BM 06.022 consists of the kringle 2 and the protease domains of human t-PA and is unglycosylated because of its expression in Escherichia coli. The pharmacokinetic properties of BM 06.022 following intravenous injection over 1 min were characterized in anesthetized male New Zealand white rabbits. BM 06.022 was injected at doses of 50, 100, 200, and 400 kU/kg bw (n = 5-6/dose). Activity concentrations in plasma were determined using an indirect spectrophotometric assay. The maximum plasma concentration and the area under the plasma concentration vs. time curve (AUC0-00) of BM 06.022 increased linearly with dose. The systemic clearance ranged from 2.5 to 3.0 ml.min-1.kg-1 and did not show dose-dependency, in contrast to alteplase which was studied at doses of 200, 400, 800, and 1600 kU/kg. A direct comparison of clearance rates of BM 06.022 and alteplase at doses of 200 and 400 kU/kg each revealed a 8.5-fold slower clearance rate of BM 06.022. The majority (18/23) of rabbits with BM 06.022 injection showed a pharmacokinetic profile which was best characterized by a one-compartment model in contrast to alteplase (10/23). The dose-groups of BM 06.022 showed an average dominant half-life ranging from 11.6 to 15.4 min, which was about five-times longer than the dominant half-life values of alteplase (2.3 to 4.5 min). Assuming a two-compartment model in the remaining animals, the initial alpha-phase of BM 06.022 accounted for 40.1 +/- 13.2% (n = 5) of the total AUC, whereas the alpha-phase of alteplase accounted for 82.7 +/- 3% (n = 13) of the total AUC.
Martin
U
U
Department of Pharmacology, Boehringer Mannheim GmbH, Germany.
Fischer
S
S
Kohnert
U
U
Rudolph
R
R
Sponer
G
G
Stern
A
A
Strein
K
K
D000818:Animals; D004926:Escherichia coli / Q000235:genetics; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006801:Humans; D008297:Male; D011817:Rabbits; D011994:Recombinant Proteins / Q000494:pharmacology; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000493:pharmacokinetics*
D005343:Fibrinolytic Agents; D011994:Recombinant Proteins; C087896:reteplase; D010959:Tissue Plasminogen Activator