Central nervous system targeting of 2',3'-dideoxyinosine via adenosine deaminase-activated 6-halo-dideoxypurine prodrugs

Morgan, Michael; C, S; Murakami, Kunio; Mitsuya, Hiroaki; Anderson, Bradley D.

doi:10.1128/aac.36.10.2156

Cited by 35 publications

(27 citation statements)

References 32 publications

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“…The sample was then resuspended in 100 l of mobile phase, and a 50-l aliquot was injected onto the HPLC system. Brain samples were treated and analyzed for nelfinavir as described by Savolainen et al and Morgan et al (8,11). Plasma, milk, and brain tissue samples were analyzed for nelfinavir using a previously reported HPLC assay (11).…”

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confidence: 99%

Role of P-Glycoprotein in Distribution of Nelfinavir across the Blood-Mammary Tissue Barrier and Blood-Brain Barrier

Edwards

Alcorn

Savolainen

et al. 2005

Antimicrob Agents Chemother

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As a first approach in understanding the possible efficacy and toxicity of human immunodeficiency virus protease inhibitors during breast feeding, the milk-to-plasma ratio of nelfinavir was determined in lactating rats. The milk-to-plasma ratio of nelfinavir was determined to be 0.56 ؎ 0.10 (means ؎ standard deviations). Western blotting indicated that P-glycoprotein is expressed in rat mammary and brain tissue; however, the multidrug-resistant modulator GF120918 showed a significant effect only at the blood-brain barrier and not at the mammary-epithelial tissue barrier.

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confidence: 99%

Role of P-Glycoprotein in Distribution of Nelfinavir across the Blood-Mammary Tissue Barrier and Blood-Brain Barrier

Edwards

Alcorn

Savolainen

et al. 2005

Antimicrob Agents Chemother

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“…Shirasaka et at. (1990) and Morgan et at. (1992) have studied 6-halogenated-2',3'-dideoxypurine analogues as lipophilic prodrugs of ddl.…”

Section: Discussionmentioning

confidence: 99%

“…Jones et a/., 1987; Lindsay et a/.3~T991) and adenosine deaminase ( Van der Weyden and Kelley, 1976;Shirasaka et a/., 1990;Morgan et a/., 1992). In efforts to design this type of prodrug, we have synthesized the prodrug 2'-f1uoro-ara-dideoxypurine (2'-F-ara-ddP), which can be converted to the active nucleoside 2'-fluoro-aradideoxyinosine (2'-F-ara-ddl).…”

Section: Discussionmentioning

confidence: 99%

“…The results obtained by these investigators suggested that the lipophilic 6-haI0-2',3'-dideoxypurine nucleosides may be useful as prodrugs for targeting ddl to the central nervous system. Morgan et al (1992) later demonstrated severe toxicity after administration of 6-F-ddP to rats. These investigators also provided evidence that 6-CI-ddP yielded greater brain concentrations of ddl than did either 6-Br-ddP or 6-I-ddP after intravenous administration to rats.…”

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confidence: 99%

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Brain Targeting of anti-HIV Nucleosides:in vitro and in vivoEvaluation of 6-chloro-2′,3′-dideoxypurine, a Lipophilic Prodrug of 2′,3′-dideoxyinosine

Doshi

Boudinot

Gallo

et al. 1994

Antivir Chem Chemother

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Lipophilic 6-halo-2′,3′-dideoxypurine nucleosides may be useful prodrugs for the targeting of 2′,3′-dideoxyinosine (ddl) to the central nervous system. The purpose of this study was to evaluate the potential effectiveness of 6-chloro-2′,3′-dideoxypurine (6-CI-ddP) for the targeting of ddl to the brain. In vitro studies indicated that the adenosine deaminase-mediated biotransformation of 6-CI-ddP to ddl was more rapid in mouse brain homogenate than in mouse serum. The brain distribution of 6-CI-ddP and ddl was assessed in vivo in mice following intravenous and oral administration of the prodrug or parent drug. Brain concentrations of ddl were similar after intravenous administration of 6-CI-ddP or ddl. However, after oral administration of the 6-CI-ddP prodrug, significantly greater concentrations of ddl were seen in the brain compared to those found after oral administration of ddl. The brain:serum AUG ratio (expressed as a percentage) of ddl after intravenous administration of 50 mg kg−1 of the active nucleoside was 3%. Following oral administration of 250 mg kg−1 ddl, low concentrations of ddl were detected in the brain. Brain:serum AUC ratios following intravenous and oral administration of the prodrug 6-CI-ddP were 19–25%. Thus, brain:serum AUC ratios were 6- to 8-fold higher after prodrug administration than those obtained after administration of the parent nucleoside. Oral administration of 6-CI-ddP yielded concentrations of ddl in the brain similar to those obtained following intravenous administration. The results of this study provide further evidence that 6-CI-ddP may be a useful prodrug for delivering ddl to the central nervous system, particularly after oral administration.

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“…The 6-halo-ddP analogs are more lipophilic than the parent drugs, as measured by n-octanol partitioning (22), and were synthesized in an attempt to improve the penetration of ddG and ddI into the CNS (17,21,22). Studies in rodents have demonstrated enhanced penetration of the 6-halo-ddP prodrugs into the CNS as well as enhanced penetration of ddG and ddI, presumably as a result of dehalogenation of the 6-halo-ddPs by adenosine deaminase in the CNS (ADA) (16,22). …”

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confidence: 99%

Pharmacokinetics of dideoxypurine nucleoside analogs in plasma and cerebrospinal fluid of rhesus monkeys

Hawkins

Mitsuya

McCully

et al. 1995

Antimicrob Agents Chemother

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The pharmacokinetics of 2,3-dideoxyadenosine (ddA), didanosine, 2,3-dideoxyguanosine (ddG), and 6-halogenated prodrugs of ddG, 6-chloro-ddG and 6-iodo-ddG, in plasma and cerebrospinal fluid (CSF) were studied in a non-human primate model. ddA was rapidly and completely deaminated to didanosine, such that didanosine concentration profiles in plasma and CSF were identical following administration of ddA and didanosine. The mean clearance of didanosine was 0.50 liters/h/kg, the terminal half-life was 1.8 h, and the CSF-to-plasma ratio was 4.8%. The disposition of ddG was similar, with a clearance of 0.70 liters/h/kg and a half-life of 1.7 h. The adenosine deaminase-mediated conversion of the 6-halogenated-ddG prodrugs to ddG was rapid but incomplete (48% for 6-chloro-ddG and 29% for 6-iodo-ddG). The CSF-to-plasma ratios of ddG with equimolar doses of ddG, 6-chloro-ddG, and 6-iodo-ddG were 8.5, 24, and 17%, respectively, but the actual ddG exposures in CSF (area under the CSF concentration-time curve) were comparable for ddG (12.1 M ⅐ h) and the 6-halogenated-ddG prodrugs (18.8 M ⅐ h for 6-chloro-ddG, 9.3 M ⅐ h for 6-iodo-ddG). 6-Chloro-ddG was not detectable in plasma or CSF, and the CSF-to-plasma ratio of 6-iodo-ddG was 9.4%, so the higher CSF-to-plasma ratios of ddG with the administration of the 6-halogenated-ddG prodrugs does not appear to be the result of enhanced penetration of the prodrug and subsequent dehalogenation to ddG. The penetration of ddG into CSF exceeds that of didanosine and is enhanced by administration of the 6-halogenated prodrugs, although the mechanism of this enhanced penetration is unclear.The devastating effects of human immunodeficiency virus encephalopathy underscore the importance of finding new antiretroviral agents which penetrate into the central nervous system (CNS) to treat this important component of the disease (7). The currently approved antiretroviral drugs in clinical use are dideoxynucleoside analogs, including zidovudine, zalcitabine, and didanosine (ddI) (3). We previously studied the penetration of a series of dideoxypyrimidine nucleoside analogs into cerebrospinal fluid (CSF) and demonstrated that it ranged from over 20% for zidovudine to less than 5% for zalcitabine and that the degree of penetration into CSF was determined by the nucleobase rather than the alterations to the ribose sugar (5). In addition, in subsequent clinical trials the degree of drug penetration into CSF appeared to correlate with efficacy in treating AIDS dementia (19,20).A number of dideoxypurine (ddP) nucleoside analogs have also demonstrated antiretroviral activity in in vitro screening assays (14,15,17,21), and ddI was recently approved for clinical use. 2Ј,3Ј-Dideoxyadenosine (ddA) has a degree of activity similar to that of ddI, but it is almost instantaneously deaminated to ddI in vivo (9). A series of 6-halogenated 2Ј,3Ј-dideoxyguanosine (ddG) and ddI analogs which act as prodrugs of ddG and ddI are currently in the preclinical phase of drug development. The 6-halo-ddP analogs are more lip...

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Central nervous system targeting of 2',3'-dideoxyinosine via adenosine deaminase-activated 6-halo-dideoxypurine prodrugs

Cited by 35 publications

References 32 publications

Role of P-Glycoprotein in Distribution of Nelfinavir across the Blood-Mammary Tissue Barrier and Blood-Brain Barrier

Role of P-Glycoprotein in Distribution of Nelfinavir across the Blood-Mammary Tissue Barrier and Blood-Brain Barrier

Brain Targeting of anti-HIV Nucleosides:in vitro and in vivoEvaluation of 6-chloro-2′,3′-dideoxypurine, a Lipophilic Prodrug of 2′,3′-dideoxyinosine

Pharmacokinetics of dideoxypurine nucleoside analogs in plasma and cerebrospinal fluid of rhesus monkeys

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