Transport characteristics of the anti-human immunodeficiency virus nucleoside analog, abacavir, into brain and cerebrospinal fluid

The role of the blood-brain and blood-cerebrospinal fluid (CSF) barriers in the distribution of anti-human immunodeficiency virus (HM drugs is integra l to the design of effective treatment regimens for HIV infection within th e brain. Abacavir (formerly 1592U89) is a nucleoside analog reverse transcr iptase inhibitor, which has activity against HIV. The ability of this drug to reach the brain at therapeutic concentrations has been explored by means of an established bilateral in situ brain perfusion model in combination w ith high-performance liquid chromatography analysis in the anesthetized gui nea pig. The influence of other drugs on the entry of abacavir into the bra in was also investigated and is of special significance with the use of thr ee of more anti-HIV drugs as the recommended treatment for HIV infection. T he results of this study indicate that intact [C-14]abacavir can cross the blood-brain and blood-CSF barriers and enter the brain and cisternal CSF. F urther studies, at a perfusion time of 10 min, revealed that the uptake (R- cerebrum) of this C-14-labeled drug (10.1 +/- 0.6%) was not affected by the presence of 0.86 to 200 muM unlabeled abacavir (6.8 muM; 11.0 +/- 1.4%), t he nucleoside transport inhibitor [10 muM 6-(4-nitrobenzyl)thiO-9-beta -D-r ibofuranosylpurine; 9.7 +/- 3.3%], or a substrate for the nucleobase transp orter (100 muM adenine; 12.7 +/- 3.0%). This would suggest that the entry o f abacavir into the brain would not be affected by the presence of other an ti-HIV drugs. The results of this animal study indicate that abacavir would be a useful addition to a treatment regimen against HIV-infection within t he brain.