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Abstract

To determine if there is active efflux of zidovudine (ZDV) and 2',3'-dideoxyinosine (ddI) out of the cerebrospinal fluid (CSF), and if this efflux is saturable, we investigated the steady-state CSF/plasma concentration ratio of the two drugs when administered alone or in combination. Constant-rate infusions of ZDV, ddI or both were administered to seven macaques (Macaca nemestrina) through a chronic venous catheter for a minimum of 28 hr. Antipyrine, a marker of passive diffusion, was coinfused in all experiments. Blood (5 mL) and CSF samples (0.5-1 mL) were collected by venous and lumbar/thoracic punctures, respectively, at 24 and 28 hr after beginning the infusion. When ZDV and ddI were administered alone, the steady-state CSF/plasma concentration ratios were significantly different from unity (ZDV, 0.20 +/- 0.08; ddI, 0.09 +/- 0.04) and were independent of the plasma concentration (P > 0.05). In contrast, the CSF/plasma concentration ratio of antipyrine (0.82 +/- 0.19) was close but significantly smaller than unity (P > 0.05). The CSF/plasma concentration ratios after simultaneous administration of ZDV and ddI were not significantly different (P > 0.05) from those obtained after administration of the drugs alone. These results suggest that ZDV and ddI are actively transported out of the CSF; however, within the concentration range studied, this efflux is neither saturable nor mutually competitive. Concomitant administration of ZDV and ddI did not produce a systemic interaction in the animals, indicating that the pharmacokinetics of either drug is unaffected by the presence of the other.

In Vitro and in Vivo Evaluation of 6-Azido-2‘,3‘-dideoxy-2‘-fluoro-β-d-arabinofuranosylpurine and N6-Methyl-2‘,3‘-dideoxy-2‘-fluoro-β-d-arabinofuranosyladenine as Prodrugs of the Anti-HIV Nucleosides 2‘-F-ara-ddA and 2‘-F-ara-ddI

“…Furthermore, there is evidence that ddI enters the central nervous system and the cerebrospinal fluid (CSF) less readily than AZT. The extent of ddI uptake in brain tissue and CSF relative to that in plasma was only 4.7 and 1.5%, respectively. − …”