Pharmacokinetics and tissue diffusion of ganciclovir in mice and rats.
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.



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.



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 h followed by a gradual decrease. In adult mice, the concentration peaked at 1 h, but became undetectable by 2 h after injection. Counts of white blood cells, red blood cells and platelets decreased significantly in ganciclovir-treated newborn mice.



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.
PROTECT, INSERM, Unversité Paris Diderot, Sorbonne Paris Cité, Paris, France.
Imène
I
Boujemla
Department of Paediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debre, Paris, France.
May
M
Fakhoury
PROTECT, INSERM, Unversité Paris Diderot, Sorbonne Paris Cité, Paris, France.
Michel
M
Nassar
PROTECT, INSERM, Unversité Paris Diderot, Sorbonne Paris Cité, Paris, France.
Homa
H
Adle-Biassette
Department of Paediatric Hematology, Hôpital Robert Debre, Paris, France.
Marie-Françoise
MF
Hurteaud
Department of Paediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debre, Paris, France.
Evelyne
E
Jacqz-Aigrain
PROTECT, INSERM, Unversité Paris Diderot, Sorbonne Paris Cité, Paris, France; Centre for the Developing Brain, Department of Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London SE1 7EH, United Kingdom.
Pierre
P
Gressens
PROTECT, INSERM, Unversité Paris Diderot, Sorbonne Paris Cité, Paris, France. Electronic address: natacha.teissier@rdb.aphp.fr.
Natacha
N
Teissier
D000367:Age Factors; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D015415:Biomarkers; D005260:Female; D015774:Ganciclovir / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007267:Injections; D051379:Mice; D011247:Pregnancy; D051381:Rats; D014018:Tissue Distribution
D000998:Antiviral Agents; D015415:Biomarkers; D015774:Ganciclovir