Pharmacokinetics and tissue diffusion of ganciclovir in mice and rats
Résumé
Background:
Congenital cytomegalovirus (CMV) infection is the leading infectious cause of birth defects,
mental retardation and non-genetic sensorineural hearing loss. Murine models have been
developed in order to understand the pathophysiological mechanisms underlying these
lesions. These models are being proposed for the validation of therapeutic protocols for
clinical use. The aim of this preclinical study was to assess the pharmacokinetics of the
reference antiviral molecule, ganciclovir, in order to optimize these protocols and confirm the
diffusion of the molecule to the appropriate target zones.
Methods:
Transplacental and intracochlear diffusion of ganciclovir was evaluated in mice and rats.
Pharmacokinetics was assessed in adult mice and pups after 5 consecutive days of
intraperitoneal injection of ganciclovir. The occurrence of hematological side effects of
ganciclovir was evaluated in the different blood cell lineages.
Results:
In adult rats, the intracochlear diffusion of ganciclovir was shown to achieve the same
concentration as in blood. In gestating mice, transplacental diffusion was observed, with a
fetal-to-maternal blood ratio of 0.5. In newborn mice, the plasma concentration profile of
ganciclovir showed a peak at 2 hours followed by a gradual decrease. In adult mice, the
concentration peaked at 1 hour, but became undetectable by 2 hours after injection. Counts of white blood cells, red blood cells and platelets decreased significantly in
ganciclovir-treated newborn mice.
Conclusion:
Our data provide evidence for the intracochlear diffusion of the molecule, which may be
relevant for the treatment of sensorineural hearing loss in congenitally-infected children.
Origine : Fichiers produits par l'(les) auteur(s)
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