Evaluation of the pharmacokinetic features and tissue distribution of the potent nonnucleoside inhibitor of HIV-1 reverse transcriptase, N-[2-(2-fluorophenethyl)]-N'-[2-(5-bromopyridyl)]-thiourea (HI-240) with an analytical HPLC method.
OBJECTIVE
The purpose of the present study was to examine the pharmacokinetic features and tissue distribution of N-[2-(2-fluorophenethyl)]-N'-[2-(5-bromopyridyl)]-thiourea (HI-240), a novel non-nucleoside inhibitor of HIV reverse transcriptase with potent anti-viral activity against AZT-sensitive as well as multidrug-resistant HIV-1 strains.


METHODS
A sensitive and accurate high performance liquid chromatography (HPLC)-based quantitative detection method was established to measure concentrations of HI-240 in pharmacokinetic studies. The plasma concentration-time data were modeled by using the WinNonlin program to estimate the pharmacokinetic parameter values.


RESULTS
HI-240 had an elimination half-life of 78.3 +/- 2.0 min after i.v. administration and 196.8 +/- 3.1 min after i.p. administration. The systemic clearance of HI-240 was 2194 +/- 61 ml/h/kg after i.v. administration and 9339 +/- 1160 ml/h/kg after i.p. administration. Following i.v. injection, HI-240 rapidly distributed to and accumulated in multiple tissues with particularly high accumulation in adipose tissue, adrenal gland, and uterus+ovary. The concentration of HI-240 in brain tissue was comparable to that in the plasma, indicating that HI-240 easily crosses the blood-brain-barrier. Following i.p. injection, HI-240 was rapidly absorbed with a t1/2ka and a tmax values of less than 10 min. Following oral administration, HI-240 was absorbed with a t1/2ka of 4.2 +/- 1.1 min and a tmax of 95.1 +/- 25.1 min. The intraperitoneal bioavailability was estimated at 23.5%, while the oral bioavailability was only 1%.


CONCLUSIONS
The HPLC-based accurate and precise analytical detection method and pilot pharmacokinetic studies described herein provide the basis for advanced preclinical pharmacodynamic studies of HI-240. The ability of HI-240 to distribute rapidly and extensively into extravascular compartments and easily cross the blood-brain barrier represent significant pharmacokinetic advantages over AZT.
Chen
C L
CL
Department of Pharmaceutical Sciences, Hughes Institute, St. Paul, Minnesota 55113, USA.
Uckun
F M
FM
D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004355:Drug Stability; D005069:Evaluation Studies as Topic; D005260:Female; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007262:Infusions, Intravenous; D007274:Injections, Intraperitoneal; D051379:Mice; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013890:Thiourea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D014018:Tissue Distribution
C119306:HI 240; D011725:Pyridines; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; D013890:Thiourea