Pharmacokinetic analysis for the development of new potent anti-HIV-1 agents, the KR-V series

새로운 항HIV-1제, KR-V series의 개발을 위한 약물동태연구

  • Lee, Young-mi (Department of Pharmacokinetics & Toxicokinetics, Korea Research Institute of Chemical Technology) ;
  • Kim, Jin-suk (College of Veterinary Medicine, Konkuk University) ;
  • Han, Sang-seop (Department of Pharmacokinetics & Toxicokinetics, Korea Research Institute of Chemical Technology) ;
  • Shin, Ho-chul (Department of Pharmacokinetics & Toxicokinetics, Korea Research Institute of Chemical Technology)
  • 이영미 (한국화학연구소 약물독성동태연구실) ;
  • 김진석 (건국대학교 수의과대학) ;
  • 한상섭 (한국화학연구소 약물독성동태연구실) ;
  • 신호철 (한국화학연구소 약물독성동태연구실)
  • Received : 2000.06.10
  • Published : 2000.09.25

Abstract

The pharmacokinetic properties of KR-V compounds, recently developed as new anti-HIV agents, were studied after i.v. and p.o. administration in rats. The concentrations of the KR-V series were determined in rat plasma using an high-performance liquid chromatography (HPLC)-UV detection system. Of the 19 KR-V compounds investigated in the present study, only KR-V 3, 10, 14, 16 and 18-1 showed oral bioavailability. The plasma concentration-time data could be adequately described by an one-compartment open model. In the i.v. kinetic study (10mg/kg), the CLt of KR-V 3, 10, 14 and 16 (>4L/hr/kg) were significantly higher than that of KR-V 18-1 (1.1 L/hr/kg). The AUC of KR-V 18-1 was greater ($8.97{\mu}g{\cdot}hr/ml$) than that of the other compounds, but the Vd (0.58 L/kg) was lower. In the p.o. kinetic study (50mg/kg), although the t-1/2 of KR-V 18-1 was shorter than that of the other compounds, the AUC ($3.659{\mu}g{\cdot}hr/ml)$ and $C_{max}(1.891{\mu}g/ml$) were markedly higher. In a seperated in vitro experiment, only KR-V 18-1, of the 5 compounds with bioavailibility, exhibits potent activity against HIV-1 mutant strains. Therefore, KR-V 18-1 is expected to become a new potent anti-AIDS drug candidate/lead compound.