Influence of hepatic and renal failure on pharmacokinetic properties of the novel recombinant plasminogen activator BM 06.022 in rats.
BM 06.022 is a novel recombinant, unglycosylated plasminogen activator comprising only the kringle 2 and protease domains of human tissue-type plasminogen activator (t-PA), and it has a longer half-life than t-PA. Because t-PA is mainly cleared by the liver, rat models of hepatic and renal insufficiency were used to identify the main catabolic organ of BM 06.022, compared with alteplase (recombinant t-PA). Hepatic insufficiency in rats was chemically induced by pretreatment with carbon tetrachloride for 1 day; renal insufficiency was achieved by acute bilateral, surgical nephrectomy. Plasma concentration of functionally active BM 06.022 or alteplase was measured by an indirect spectrophotometric assay. Intravenous administration of 200 kU/kg of BM 06.022 or alteplase over 15 sec to rats with hepatic failure or olive oil pretreatment as control did not significantly alter the total plasma clearance (CL) of BM 06.022 vs. control (4.9 +/- 0.5 vs. 5.7 +/- 0.5 ml.min-1 x kg-1, NS) in contrast to alteplase (32.1 +/- 6.5 vs. 82.3 +/- 12.9 ml.min-1 x kg-1, p < 0.05). Renal insufficiency increased the CL of BM 06.022 vs. sham surgery (3.1 +/- 0.4 vs. 6.3 +/- 0.5 ml.min-1 x kg-1, p < 0.05) in contrast to alteplase (33.2 +/- 5.2 vs. 37.2 +/- 7.2 ml.min-1 x kg-1, NS). In vitro incubation of 2000 U/ml BM 06.022 or alteplase in citrate blood and plasma demonstrated a decrease of the plasma concentration with a shorter (p < 0.001) half-life for BM 06.022 than for alteplase in blood (71.9 +/- 3.1 vs. 130 +/- 3.3 min) and in plasma (62.9 +/- 1.2 vs. 129.9 +/- 5.3 min).(ABSTRACT TRUNCATED AT 250 WORDS)
Martin
U
U
Department of Pharmacology, Boehringer Mannheim GmbH, Mannheim, Germany.
Sponer
G
G
Strein
K
K
D058186:Acute Kidney Injury / Q000378:metabolism*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002252:Carbon Tetrachloride Poisoning / Q000378:metabolism; D005260:Female; D005343:Fibrinolytic Agents / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D017093:Liver Failure / Q000378:metabolism*; D008297:Male; D009392:Nephrectomy; D010960:Plasminogen Activators / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000493:pharmacokinetics; D013448:Sulfobromophthalein / Q000032:analysis; D010959:Tissue Plasminogen Activator / Q000493:pharmacokinetics*
D005343:Fibrinolytic Agents; D011994:Recombinant Proteins; D013448:Sulfobromophthalein; C087896:reteplase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator