Central nervous system targeting of 2',3'-dideoxyinosine via adenosine deaminase-activated 6-halo-dideoxypurine prodrugs.
Central nervous system targeting of 2',3'-dideoxyinosine via adenosine deaminase-activated 6-halo-dideoxypurine prodrugs.
复制标题
通过腺苷脱氨酶激活的 6-卤代-二脱氧嘌呤前药靶向 2,3-二脱氧肌苷的中枢神经系统。
DOI：
10.1128/aac.36.10.2156
复制
发表时间：
1992
影响因子：
4.9
通讯作者：
Anderson,BD
中科院分区：
文献类型：
--
作者：
Morgan,ME;Chi,SC;Murakami,K;Mitsuya,H;Anderson,BD
AIDS dementia complex is a neurologic disorder, characterized by increasingly severe cognitive, behavioral, and motor impairment, which is associated with human immunodeficiency virus (HIV) infection in the central nervous system (CNS). Many of the dideoxynucleosides effective systemically in the treatment of HIV infections, such as 2',3'-dideoxyinosine (ddI), exhibit limited penetration into the CNS and limited or variable effectiveness in reversing the symptoms of AIDS dementia. Thus, approaches for increasing the CNS uptake of ddI and other dideoxynucleosides are needed. The CNS uptake of a series of 6-halo-2',3'-dideoxypurine ribofuranosides (6-halo-ddPs) previously shown to be active against HIV because of their conversion to ddI through the action of adenosine deaminase was examined in rats. In vitro studies in rat blood and brain tissue homogenate suggested a favorable selectivity for bioconversion in brain tissue, but with bioconversion half-lives varying widely within the series. In vivo infusions of 6-chloro-ddP (6-Cl-ddP), 6-bromo-ddP (6-Br-ddP), and 6-iodo-ddP (6-I-ddP) resulted in significant increases (20- to 34-fold) in the ddI concentration ratios in brain parenchyma/plasma when compared with those after an infusion of ddI alone. Absolute concentrations of ddI in brain parenchyma were increased 10- and 4-fold, respectively, following 30-min infusions of 6-Cl-ddP or 6-Br-ddP, but were 2.4-fold lower after an infusion of 6-I-ddP relative to that after a control infusion of ddI. Detailed studies of the plasma pharmacokinetics, CNS uptake kinetics, and bioconversion of 6-Cl-ddP were conducted to compare in vivo transport and bioconversion parameters with those predicted from in vitro measurements and to rationalize the efficiency of CNS delivery of ddI from 6-Cl-ddP. The results show that increased lipophilicity alone does not ensure that a given prodrug will deliver higher levels of a parent compound to the CNS. Both the selectivity and absolute rate of bioconversion in the brain are important factors.
