title: Influence of the degree of renal dysfunction on the pharmacokinetic properties of the novel recombinant plasminogen activator reteplase in rats.
abstract: Reteplase (drug code: BM 06.022) is an unglycosylated recombinant plasminogen activator variant derived from human tissue-type plasminogen activator. The main metabolic organs of reteplase are the kidneys, liver, and blood, whereas human tissue-type plasminogen activator is predominantly cleared by the liver. Recent studies showed that reteplase plasma concentrations were significantly increased in severe acute renal failure. The purpose of the present study was to evaluate whether the degree of renal failure influences the pharmacokinetic properties of reteplase. Subacute renal failure in rats was induced by bilateral 1-hr clamping of the renal arteries and recovery for 3 or 6 days. Acute renal failure was induced by bilateral surgical nephrectomy. Renal function was assessed by inulin clearance. The plasma concentration of functionally active reteplase was measured by an indirect spectrophotometric assay. Reteplase was administered as a double-bolus intravenous injection of 140 + 140 kU/kg, 30 min apart. In comparison with sham surgery, 1-hr clamping plus recovery for 6 days had the least effect on inulin clearance, followed by clamping and recovery for 3 days and bilateral nephrectomy (20.2 +/- 1.8 vs. 13.0 +/- 1.3, 8.3 +/- 0.8, and 3.1 +/- 0.2 ml center dot min-1 center dot kg-1, p < 0.01). Total plasma clearance of reteplase was significantly reduced, compared with sham surgery after 1-hr clamping plus 3-day recovery and bilateral nephrectomy (3.65 +/- 0.26 vs. 2.6 +/- 0.23 and 2.18 +/- 0.14 ml center dot min-1 center dot kg-1, p < 0.05 and p < 0.01, respectively), but not after 1-hr clamping plus 6-day recovery (3.33 +/- 0.34 ml center dot min-1 center dot kg-1, NS vs. sham surgery). There was a significant (p < 0.0001) linear correlation (r = 0.713) between the decrease of inulin clearance and the decrease of reteplase clearance. These data indicate that slight impairment of renal function does not significantly influence pharmacokinetic properties of reteplase, whereas severe renal dysfunction does.
authors.affiliation: Department of Pharmacology, Boehringer Mannheim GmbH, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Martin
authors.forename: L
authors.initials: L
authors.lastname: Doerge
authors.forename: K
authors.initials: K
authors.lastname: Stegmeier
authors.forename: B
authors.initials: B
authors.lastname: Müller-Beckmann
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism*; D000818:Animals; D005343:Fibrinolytic Agents / Q000097:blood / Q000493:pharmacokinetics*; D007444:Inulin / Q000652:urine; D007677:Kidney Function Tests; D008297:Male; D010960:Plasminogen Activators / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000097:blood / Q000493:pharmacokinetics; D010959:Tissue Plasminogen Activator
chemical_list: D005343:Fibrinolytic Agents; D011994:Recombinant Proteins; D007444:Inulin; C087896:reteplase; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator