In vivo toxicity, pharmacokinetic features and tissue distribution of N-[2-(2,5-dimethoxyphenylethyl)]-N '-[2-(5-bromopyridyl)]-thiourea (HI-236), a potent non-nucleoside inhibitor of HIV-1 reverse transcriptase

N-[2-(2,5-Dimethoxyphenylethyl)]-N'-[2-(5-bromopyridyl)]-thiourea (HI-236, CAS 233271-65-3) possesses potent anti-viral activity against zidovudine-se nsitive as well as multidrug-resistant HIV-1 (human immunodeficiency virus) strains. The purpose of the present study was to examine in vivo toxicity, pharmacokinetic features and tissue distribution of HI-236 in mice. HI-236 had an elimination half-life of 85.8 min after i.v. administration and 86. 6 min after i.p. administration. The systemic clearance of HI-236 was 4337 ml/h/kg after i.v. administration and 10130 ml/h/kg after i.p. administrati on. Following i.v. injection, HI-236 rapidly distributed to and accumulated in multiple tissues with particularly high accumulation in lung, adipose t issue, skin, urinary bladder, adrenal gland and uterus + ovary. The concent ration of HI-236 In brain tissue was comparable to that in the plasma, indi cating that HI-236 easily crosses the blood-brain barrier. Following i.p. i njection, HI-236 was rapidly absorbed with a t(max) values of 5.6 min and s howed linear pharmacokinetics within the dose range of 10-80 mg/kg. Followi ng oral administration, HI-236 was absorbed with a t(max) of 5.8 min. The i ntraperitoneal bioavailability was estimated at 42.9 %, while the oral bioa vailability was only 2.2 %. The pharmacokinetic study described herein prov ides the basis for advanced pharmacodynamic study of HI-236.