The role of the blood-brain and blood-cerebrospinal fluid (CSF) barriers in the distribution of anti-human immunodeficiency virus (HIV) drugs is integral to the design of effective treatment regimens for HIV infection within the brain. Abacavir (formerly 1592U89) is a nucleoside analog reverse transcriptase 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 with high-performance liquid chromatography analysis in the anesthetized guinea pig. The influence of other drugs on the entry of abacavir into the brain was also investigated and is of special significance with the use of three of more anti-HIV drugs as the recommended treatment for HIV infection. The results of this study indicate that intact [(14)C]abacavir can cross the blood-brain and blood-CSF barriers and enter the brain and cisternal CSF. Further studies, at a perfusion time of 10 min, revealed that the uptake (R(cerebrum)) of this (14)C-labeled drug (10.1 +/- 0.6%) was not affected by the presence of 0.86 to 200 microM unlabeled abacavir (6.8 microM; 11.0 +/- 1.4%), the nucleoside transport inhibitor [10 microM 6-(4-nitrobenzyl)thio-9-beta-D-ribofuranosylpurine; 9.7 +/- 3.3%], or a substrate for the nucleobase transporter (100 microM adenine; 12.7 +/- 3.0%). This would suggest that the entry of abacavir into the brain would not be affected by the presence of other anti-HIV drugs. The results of this animal study indicate that abacavir would be a useful addition to a treatment regimen against HIV-infection within the brain.