Pharmacological survey of recombinant hirudin.
The pharmacological properties of a genetically engineered recombinant hirudin (r-hirudin) were studied in animal experiments. r-Hirudin proved to be a well tolerated substance. I.v. injection of up to 200 mg/kg did not lead to perceptible functional or morphological changes. There were no treatment-related effects on the cardiovascular system of dogs and rats after administration of up to 10 mg/kg. After long-term treatment (4 weeks, 1.0 mg/kg daily), no r-hirudin-related histopathological, haematological or biochemical changes could be found. Formation of antibodies was not detectable. Absorption, distribution, and elimination of r-hirudin were studied in dogs and rats. Pharmacokinetics could be best described by an open two-compartment model with first-order kinetics. After i.v. injection in dogs, r-hirudin is distributed into the extracellular space and eliminated through the kidneys in active form by glomerular filtration. After i.v. administration, a half-life of about 1 h was estimated; s.c. administration prolonged the apparent half-life. Pulmonary absorption was shown. Enteral absorption, placental transfer as well as transfer through the fetal integument were very low. r-Hirudin did not pass the blood-brain barrier. The efficacy of r-hirudin in preventing both venous and arterial thrombosis, vascular shunt occlusion or disseminated intravascular coagulation was demonstrated in rats. Depending on the dose, r-hirudin was able to prevent or reduce stasis-induced venous thrombosis, prolong the patency of an extracorporeal arteriovenous shunt, reduce the incidence of arterial thrombosis caused by vascular wall lesions as well as of microthrombosis induced by thrombin infusion.(ABSTRACT TRUNCATED AT 250 WORDS)
Markwardt
F
F
Institute of Pharmacology and Toxicology, Medical Academy Erfurt, GDR.
Fink
G
G
Kaiser
B
B
Klöcking
H P
HP
Nowak
G
G
Richter
M
M
Stürzebecher
J
J
D000818:Animals; D001519:Behavior / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004285:Dogs; D005260:Female; D005343:Fibrinolytic Agents; D006439:Hemodynamics / Q000187:drug effects; D006470:Hemorrhage / Q000139:chemically induced; D006629:Hirudins / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D007457:Iodine Radioisotopes; D008297:Male; D008431:Maternal-Fetal Exchange; D051379:Mice; D008813:Mice, Inbred ICR; D009392:Nephrectomy; D011247:Pregnancy; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D012119:Respiration / Q000187:drug effects
D005343:Fibrinolytic Agents; D006629:Hirudins; D007457:Iodine Radioisotopes; D011994:Recombinant Proteins