Restricted Transport of 3'-Azido-3'-Deoxythymidine and Dideoxynucleosides Through the Blood-Brain Barrier

Terasaki, Toshio; Pardridge, William M.

doi:10.1093/infdis/158.3.630

Cited by 101 publications

(47 citation statements)

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“…Our results with rabbits indicated a similar peak CSF/plasma drug ratio of 0.38 at 30 min, but this ratio declined to 0.23 at 75 min after the intravenous infusion of AZT. The corresponding brain/plasma drug ratios for AZT in our experiments were 0.58 and 0.07 at 30 and 75 min, (17) provided evidence that although AZT penetrates the CSF through the blood-CSF barrier at the choroid plexus in rats, its transport through the BBB is restricted.…”

Section: Discussionsupporting

confidence: 70%

“…This observation suggested that higher-than-therapeutic doses of AZT should be given to result in adequate antiviral concentrations in the CSF, although higher doses may exacerbate AZT-induced bone marrow toxicity (15). It has been reported that, although AZT penetrates CSF through the blood-CSF barrier at the choroid plexus, its transport into the brain is restricted (17). This report supports the basic idea that CSF and brain interstitial fluid are not in equilibrium.…”

supporting

confidence: 69%

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Comparative pharmacokinetics of two prodrugs of zidovudine in rabbits: enhanced levels of zidovudine in brain tissue

Lupia

Ferencz

Lertora

et al. 1993

Antimicrob Agents Chemother

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The pharmacokinetics of two prodrugs of zidovudine (AZT), 1,4-dihydro-1-methyl-3-[(pyridylcarbonyl)oxy] ester and isoleucinyl ester (DPAZT and LAZT, respectively), were investigated in a rabbit model to determine their potential utility as drugs against human immunodeficiency virus. Drugs were administered by intravenous infusion over 5 min at doses equal to 10 mg of AZT per kg of body weight. The levels of the prodrugs and of released AZT in plasma, cerebrospinal fluid (CSF), and brain were determined by high-performance liquid chromatography analysis. DPAZT disappeared rapidly from plasma, whereas IAZT maintained a sustained level in plasma for up to 4 h. The levels in plasma of AZT released from DPAZT were consistently lower than the levels of AZT released from IAZT or AZT itself. At 75 min after infusion of AZT, DPAZT, and IAZT, the CSF plasma AZT ratios were 0.23, 0.30, and 0.25, while the brain/CSF AZT ratios were 0.32, 0.63, and 0.64, respectively. These results indicate that the administration of each of the prodrugs produced a higher concentration of AZT in the brain than did the direct administration of AZT. Both prodrugs therefore may be superior to AZT itself with respect to achieving anti-human immunodeficiency virus concentrations within the central nervous system.

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Section: Discussionsupporting

confidence: 70%

supporting

confidence: 69%

Comparative pharmacokinetics of two prodrugs of zidovudine in rabbits: enhanced levels of zidovudine in brain tissue

Lupia

Ferencz

Lertora

et al. 1993

Antimicrob Agents Chemother

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“…In addition to mutations previously associated with zidovudine resistance, three sequences contained the mutation 215 ~hr~Asp, the phenotype of which is unknown. Zidovudine sensitive genotypes persisted in the brain of this patient, and this might suggest that zidovudine did not reach inhibitory concentrations within this organ due to restricted transport across the blood brain barrier or from the cerebro-spinal fluid to the brain (Klecker et al, 1987;Terasaki & Pardridge, 1988;Lupia et al, 1993). The presence of zidovudine resistant genotypes in the cerebro-spinal fluid has been reported (di Stefano et al, 1993), although at present it is not clear whether this population is representative of that found in the brain.…”

Section: Analyses Of R T Coding Regionsmentioning

confidence: 72%

Concurrent evolution of regions of the envelope and polymerase genes of human immunodeficiency virus type 1 observed during zidovudine (AZT) therapy

Sheehy

Desselberger²,

Whitwell³

et al. 1996

Journal of General Virology

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Nucleotide sequences of regions of the envelope (env) and polymerase (po/) genes of human immunodeficiency virus type 1 (HIV-1) proviral DNA were obtained from sequential blood and autopsy samples from an AIDS patient who had been treated with zidovudine for 9 months, Phylogenetic analyses showed that a reduction in genetic heterogeneity of the env regions of viruses present in the proviral blood population occurred during therapy, and this coincided with an increased pol gene heterogeneity. Differences were observed in different organs obtained post mortem for both the env and pol coding regions. The cardiac blood proviral population consisted mainly of variants which possessed sequences containing mutations at position 215 of the pol gene, associated with drug resistance. By contrast, the brain population consisted entirely of zidovudine sensitive genotypes, and this organ also harboured variants with genetically distinct env sequences. The lymph tissues obtained after death held more diverse proviral env and pol populations, containing both zidovudine sensitive and resistant genotypes.

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“…The present study was in part undertaken to clarify the discrepancy observed in rat studies between those using microdialysis (20) and whole-tissue measurements (6,21) and also the discrepancy between human (8) and rat (6) CSF (20). Together, these data suggest that the extracellular concentration of zidovudine in the brain is highest in humans, intermediate in monkeys, and lowest in rats.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, good distribution in the brain is desirable since a major clinical problem in the management of AIDS is the presence of neuropsychiatric symptoms (10). Previous studies of zidovudine distribution have used measurement of cerebrospinal fluid (CSF) in humans (8) or the intracarotid/first pass extraction technique to study blood-brain barrier permeability (21). In the present study we used the microdialysis method for measuring free (not protein-bound) extracellular tissue concentrations of drugs in the brain and other tissues (18) comparison between FLT and zidovudine with respect to AUC was made by Student's t test.…”

mentioning

confidence: 99%

Penetration of zidovudine and 3'-fluoro-3'-deoxythymidine into the brain, muscle tissue, and veins in cynomolgus monkeys: relation to antiviral action

Ljungdahl-Ståhle

Guzenda

Böttiger

et al. 1992

Antimicrob Agents Chemother

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Cynomolgus monkeys had microdialysis probes implanted under ketamine anesthesia into peripheral veins, thigh muscles, and the brain in order to sample the extracellular fluid for the concentrations of unbound nucleoside analogs. A dose of 25 mg of zidovudine or 3'-fluoro-3'-deoxythymidine (FLT) per kg was administered subcutaneously to each of three animals. Relatively high antiviral concentrations of FLT Microdialysis. Anesthesia was induced by and maintained with ketamine given intravenously. The monkeys were placed in a stereotaxic instrument. In each monkey two microdialysis probes (CMA/10; CMA Microdialysis AB, Stockholm, Sweden) with a diffusible area of 10.0 by 0.5 mm (length by outer diameter) were implanted bilaterally into the striatum through a guide cannula which was secured to the skull bone by means of an acrylic dental cement. Two microdialysis probes were also implanted in muscle tissue in the thigh, and two probes were implanted into a dorsal superficial vein of the lower limb. Duplicate probes were used to prevent loss of data. Dialysates were collected in 20-min fractions and covered with tube caps. After implantation, each microdialysis probe was perfused for 60 min with degassed Ringer solution (ACO, Stockholm, Sweden) at a constant flow rate of 2.0 pl/min. Next, to determine the recovery over the dialysis membrane in vivo, each probe was perfused with a 10 ,uM solution of zidovudine or FLT at the same rate for 60 min and then the perfusion medium was switched back to Ringer solution for a washout period. The loss of drug to the tissue by diffusion over the dialysis membrane was measured as the difference between the drug concentration in the perfusion medium (10 ,uM) and the drug concentration in the dialysate. The proportion of drug lost over the dialysis membrane was used as an estimate of the in vivo recovery (18). After the washout period of 60 min,

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Restricted Transport of 3'-Azido-3'-Deoxythymidine and Dideoxynucleosides Through the Blood-Brain Barrier

Cited by 101 publications

References 0 publications

Comparative pharmacokinetics of two prodrugs of zidovudine in rabbits: enhanced levels of zidovudine in brain tissue

Comparative pharmacokinetics of two prodrugs of zidovudine in rabbits: enhanced levels of zidovudine in brain tissue

Concurrent evolution of regions of the envelope and polymerase genes of human immunodeficiency virus type 1 observed during zidovudine (AZT) therapy

Penetration of zidovudine and 3'-fluoro-3'-deoxythymidine into the brain, muscle tissue, and veins in cynomolgus monkeys: relation to antiviral action

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