Approaches toward the optimization of CNS uptake of anti-AIDS agents

Abstract

A common neurologic disorder occurring in patients with AIDS is a progressive dementia, referred to as AIDS dementia complex, characterized by increasingly severe cognitive, behavioral and motor impairment. The progression of this disorder is associated with the presence and replication of HIV in the central nervous system (CNS). Many of the dideoxynucleosides effective in the treatment of HIV infections are quite polar molecules and exhibit limited penetration into the CNS. Studies in our laboratories in rats have shown that the steady-state concentration of 2',3'-dideoxyinosine (ddI) in the cerebrospinal fluid is less than 2% of the simultaneously determined plasma concentration, indicating that approaches to increase the CNS uptake of ddI and other dideoxynucleosides are needed. A compartmental model has been developed to describe the pharmacokinetics and CNS uptake of ddI and to simulate various approaches for increased delivery of ddI to the CNS. Two general approaches considered are inhibition of the rate of efflux from the cerebrospinal fluid by coadministration of active transport inhibitors and enhancement of the rate of entry into the CNS through chemical modification (prodrugs). Model simulations suggested that increases in steady-state concentrations of ddl in cerebrospinal fluid of ≈ 5-fold could be achieved by inhibiting the rate of efflux. Coadministration of the active transport inhibitor probenecid was shown to increase ddI concentrations in cerebrospinal fluid by 5.4-fold. Much larger increases in delivery of ddI to the CNS are possible via the prodrug approach, according to model calculations, but a number of variables, including lipophilicity, bioconversion $\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}$ in brain tissue, and systemic bioconversion $\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}$, must be optimized to achieve these increases. A series of 5'-esters of ddl were shown to provide little, if any, advantage in CNS delivery due to their high ratios of bioconversion rates in plasma relative to brain tissue. A series of 6-halo-dideoxypurines, which are activated by adenosine deaminase, have been shown to undergo more rapid bioconversion to the parent drug in brain tissue than in blood. Thirty minute infusions of 6-Cl-ddP in rats resulted in ddI concentrations in cerebrospinal fluid and brain parenchyma which were 5-fold and 24-fold higher, respectively, than when ddI was administered at the same infusion rate. Model calculations suggest that further increases are possible.