Pharmacokinetics and pharmacology of hirulog-like peptide.
Hirulog-like peptide (HLP), a new thrombin peptide inhibitor, effectively reduces neointimal formation or restenosis in rat and rabbit vascular injury models. The present study investigated the pharmacokinetics and pharmacology of HLP in Sprague-Dawley (SD) rats. The input response of HLP in rats was studied using radioisotopic tracing method. Male SD rats were intravenously injected with a single dose of I-HLP (3.2, 6.4, or 12.8 mg/kg) for pharmacokinetic analysis. The concentration-time curve of I-HLP following bolus injection fitted a 3-compartment model. The half-life of HLP in rats was between 25 and 31 min following 3.2 to 12.8 mg/kg of bolus injection. Radioactivity of I-HLP was detected in all tested tissues and was most abundant in kidneys or stomachs. Blood pressure, respiratory frequency, and heart rates were not significantly altered during continuous intravenous infusion with saline or 1.6 to 3.2 mg/kg/h of HLP for 4 h. Bleeding time and activated partial thromboplastin time were significantly prolonged in rats infused with HLP compared to vehicle. ADP-induced platelet aggregation was significantly reduced in the HLP-treated groups compared with controls. The results suggest that HLP possesses first-order kinetic characteristics. HLP is secreted mainly through kidneys. Beside its anticoagulant activity, no other adverse effect was detected in SD rats receiving HLP.
Shanghai Key Laboratory of Vascular Biology at Ruijin Hospital, Shanghai Institute of Hypertension, Jiaotong University, School of Medicine, Shanghai, China.
Xiao-Feng
XF
Tang
Jun
J
Qian
Dan-Jing
DJ
Wan
Jian-Hua
JH
Zhu
Ping-Jin
PJ
Gao
Ding-Liang
DL
Zhu
Garry X
GX
Shen
D000818:Animals; D000991:Antithrombins / Q000493:pharmacokinetics / Q000494:pharmacology / Q000652:urine; D019540:Area Under Curve; D001760:Bleeding Time; D001777:Blood Coagulation / Q000187:drug effects; D005243:Feces / Q000737:chemistry; D005340:Fibrinogen / Q000032:analysis; D006629:Hirudins / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000652:urine; D008297:Male; D010314:Partial Thromboplastin Time; D010446:Peptide Fragments / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000652:urine; D010974:Platelet Aggregation / Q000187:drug effects; D011517:Prothrombin Time; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D000991:Antithrombins; D006629:Hirudins; D010446:Peptide Fragments; C479171:hirulog-like peptide; D005340:Fibrinogen