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The Pharmaceutical Society of Korea (대한약학회)
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LB30057, an Orally Effective Direct Thrombin Inhibitor, Prevents Arterial and Venous Thrombosis in Rats and Dogs

  • Park, Hee-Dong (LG Biotech Research Institute, LG Chem.) ;
  • Kim, Hee-Jin (LG Biotech Research Institute, LG Chem.) ;
  • Oh, Yeong-Soo (LG Biotech Research Institute, LG Chem.) ;
  • Kim, In-Chull (LG Biotech Research Institute, LG Chem) ;
  • Kim, Yong-Zu (LG Biotech Research Institute, LG Chem.) ;
  • Koh, Hyun-Chul (Department of Pharmacology and Institute of Biomedical Sciences, Hanyang University) ;
  • Shin, In-Chul (Department of Pharmacology and Institute of Biomedical Sciences, Hanyang University) ;
  • Lee, Yong-Hee (LG Biotech Research Institute, LG Chem.) ;
  • Lee, Chang-Ho (Department of Pharmacology and Institute of Biomedical Sciences, Hanyang University)
  • Published : 2003.03.01
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Abstract

The anti-thrombotic effects of LB30057, a direct thrombin inhibitor, were evaluated with in vivo rat and dog thrombosis models. In rats, 1 mg/kg of LB30057 inhibited half of the clot formations in the inferior vena cava at 5 minutes after intravenous application. When measured at 2 hours after oral application, 100 mg/kg prevented approximately half of the clot formations in the inferior vena cava and 50 mg/kg prolonged the mean occlusion time from $15.6{\pm}1.3$ minutes to $47.2{\pm}8.3$ minutes in the carotid artery. In dogs, the formation of thrombus in the jugular vein was reduced to half at a dose range of 20-30 mg/kg at 6 hours after oral application. In addition, the LB30057 dosage required to reduce venous clot formation by approximately 80-90% in dogs was only about 10% of that required for the same reduction in rats. This is probably due to the variation in its time-dependent blood concentration profiles in each species; for example, the plasma half-life of LB71350 in dogs was longer than that in rats ($153.0{\pm}3.0$ vs. $129.7{\pm}12.7$ min at 30 mg/kg, i.v., respectively). AUG, $T_{max},{\;}G_{max}$, and BA in dogs were 59, 8.9, 9.17, and 13.3 times higher than those in rats at oral 30 mg/kg, respectively. Taken together, these results suggest that LB30057 administered orally is effective in the prevention of arterial and venous thrombosis in rats and dogs. It therefore represents a good lead compound for investigations to discover a new, orally available, therapeutic agent for treating thrombotic diseases.

Keywords

References

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