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-sensitive 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 10,130 ml/h/kg after i.p. administration. Following i.v. injection, HI-236 rapidly distributed to and accumulated in multiple tissues with particularly high accumulation in lung, adipose tissue, skin, urinary bladder, adrenal gland and uterus + ovary. The concentration of HI-236 in brain tissue was comparable to that in the plasma, indicating that HI-236 easily crosses the blood-brain barrier. Following i.p. injection, HI-236 was rapidly absorbed with a tmax values of 5.6 min and showed linear pharmacokinetics within the dose range of 10-80 mg/kg. Following oral administration, HI-236 was absorbed with a tmax of 5.8 min. The intraperitoneal bioavailability was estimated at 42.9%, while the oral bioavailability was only 2.2%. The pharmacokinetic study described herein provides the basis for advanced pharmacodynamic study of HI-236.
Chen
C L
CL
Department of Pharmaceutical Sciences, Parker Hughes Institute, St. Paul, MN, USA.
Venkatachalam
T K
TK
Waurzyniak
B
B
Chelstrom
L
L
Uckun
F M
FM
D000818:Animals; D001682:Biological Availability; D001812:Blood-Brain Barrier / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D005260:Female; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D051379:Mice; D011725:Pyridines / Q000493:pharmacokinetics* / Q000633:toxicity*; D018894:Reverse Transcriptase Inhibitors / Q000493:pharmacokinetics* / Q000633:toxicity*; D013890:Thiourea / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000633:toxicity*; D014018:Tissue Distribution
C121245:HI 236; D011725:Pyridines; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; D013890:Thiourea