Distribution of antiviral nucleoside analogues into brain and skin
Author: Borg, Natalia
Date: 1999-01-08
Location: Föreläsningssalen R 64, Rehabgatan, plan 6, Huddinge Sjukhus
Time: 9.00
Department: Institutionen för medicinsk laboratorievetenskap och teknik / Department of Laboratory Sciences and Technology
Abstract
The aim of this thesis was to study physiological and physico-chemical
factors influencing the pharmacokinetics and distribution over the
blood-brain barrier of antiviral nucleoside analogues in the rat, and to
study the distribution to the human skin in vivo of an anti-herpetic
nucleoside analogue. Microdialysis was used to sample the free (unbound)
extracellular concentration of the nucleoside analogues from the brain
tissue, muscle and blood in the rat and from the dermis of healthy human
volunteers. Microdialysis was also used in vitro to determine the plasma
protein binding of the nucleoside analogues.
HPLC was used for analysis and quantification of the nucleoside
analogues. The HPLC assays were optimised by using PLS (Partial Least
Square analysis), which allows a rapid development of assays for new
nucleoside analogues.
The effect of varying perfusion medium osmolality on the in vivo
microdialysis recovery of caffeine and 5-chloro-2',
3'-dideoxy-3'-fluorouridine was investigated in rat brain. A linear
correlation between the recovery over microdialysis membrane and
osmolality of perfusion medium was demonstrated for both substances
within a certain interval. At higher osmolality (>627 mosmol/l) of the
perfusion medium the increase of the recovery of caffeine was non-linear,
indicating that there is an upper limit of the change in extracellular
volume in the brain.
The distribution of alovudine (3'-fluorothymidine) to the brain and to
the cerebrospinal fluid was studied after i. v. infusion and after s.c.
injection. The concentration gradient between brain extracellular fluid
and cerebrospinal fluid indicates that there is an active efflux of
alovudine from the brain. Acetazolamide, a carbonic anhydrase inhibitor,
inhibiting the cerebrospinal fluid production in the choroid plexus, had
no influence on the AUC (Area Under the plasma concentration-time Curve)
ratio brain/blood. This suggests that alovudine transport to the brain
does not occur via the cerebrospinal fluid, but via cerebrovascular
endothelium. Thymidine, administered locally or systemically, had no
influence on the AUC ratio brain/blood, indicating that thymidine
transport is not involved. Two inhibitors of transport proteins,
probenecid and quinidine, were also used to study the alovudine transport
system. Quinidine, but not probenecid, significantly decreased the
alovudine concentration in the brain and increased the concentration
gradient. Both perfusion through the microdialysis probe with alovudine
solution at increasing concentration and quirridine administration
significantly increased the microdialysis recovery of alovudine.
The distribution into the rat brain of 5-substituted alovudine analogues
and physico-chemical properties of these substances was studied and a
multivariate quantitative structure-kinetic relationship was calculated.
No correlation between the transport over the blood-brain barrier and the
lipophilicity (octanol/water partition coefficient) could be
demonstrated. Instead the pKa and the electronic distribution properties
of the 5-substituent were found to influence the concentration gradient
across the blood-brain barrier. This result indicates that alovudine
analogues are subject to active transport (carrier-mediated) rather than
passive diffusion across the blood-brain barrier.
The distribution to the brain of the cytidine analogues: 2',
3'-dideoxycytidine and 3'-hydroxymethyl-2', 3'- dideoxycytidine over the
blood-brain barrier were studied after s.c. administration. The
pharmacokinetic properties were found to be similar. There was no
significant difference with respect to blood-brain barrier transport
between 2', 3'-dideoxycytidine and 3'-hydroxymethyl-2',
3'-dideoxycytidine. Thus, the sugar structure did not influence their
transport into the brain.
The distribution to the brain of penciclovir after i.v. injection or p.o.
administration of its prodrug famciclovir and during i.v. infusion of
penciclovir or famciclovir was studied in rats. Penciclovir was found to
cross the blood-brain barrier and achieved significant concentrations in
the brain.
The distribution of penciclovir into the dermis of healthy volunteers was
studied after a single dose of its prodrug, famciclovir, by microdialysis
and by the suction blister technique. The results obtained with the
suction blister technique and by microdialysis were similar and both
showed that pencilovir reaches the skin in concentrations expected to
inhibit herpes virus replication. However, microdialysis allows
continuous sampling of the drug over a prolonged time after
administration. The microdialysis concentration was decreased by cold and
by adrenaline- mediated vasoconstriction.
Issue date: 1998-12-18
Publication year: 1999
ISBN: 91-628-3202-6
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