title: Brain bioavailability of human intravenous immunoglobulin and its transport through the murine blood-brain barrier.
abstract: Intravenous immunoglobulin (IVIg) is currently evaluated in clinical trials for the treatment of various disorders of the central nervous system. To assess its capacity to reach central therapeutic targets, the brain bioavailability of IVIg must be determined. We thus quantified the passage of IVIg through the blood-brain barrier (BBB) of C57Bl/6 mice using complementary quantitative and qualitative methodologies. As determined by enzyme-linked immunosorbent assay, a small proportion of systemically injected IVIg was detected in the brain of mice (0.009±0.001% of injected dose in the cortex) whereas immunostaining revealed localization mainly within microvessels and less frequently in neurons. Pharmacokinetic analyses evidenced a low elimination rate constant (0.0053  per hour) in the cortex, consistent with accumulation within cerebral tissue. In situ cerebral perfusion experiments revealed that a fraction of IVIg crossed the BBB without causing leakage. A dose-dependent decrease of brain uptake was consistent with a saturable blood-to-brain transport mechanism. Finally, brain uptake of IVIg after a subchronic treatment was similar in the 3xTg-AD mouse model of Alzheimer disease compared with nontransgenic controls. In summary, our results provide evidence of BBB passage and bioavailability of IVIg into the brain in the absence of BBB leakage and in sufficient concentration to interact with the therapeutic targets.
authors.affiliation: 1] Centre de Recherche du CHU de Québec, Quebec, Canada [2] Faculté de Pharmacie, Université Laval, Centre Hospitalier de l'Université Laval (CHUL) Research Center, Quebec, Canada [3] Département de Recherche et Développement, Héma-Québec, Quebec, Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: St-Amour
authors.forename: Isabelle
authors.initials: I
authors.lastname: Paré
authors.forename: Wael
authors.initials: W
authors.lastname: Alata
authors.forename: Katherine
authors.initials: K
authors.lastname: Coulombe
authors.forename: Cassandra
authors.initials: C
authors.lastname: Ringuette-Goulet
authors.forename: Janelle
authors.initials: J
authors.lastname: Drouin-Ouellet
authors.forename: Milène
authors.initials: M
authors.lastname: Vandal
authors.forename: Denis
authors.initials: D
authors.lastname: Soulet
authors.forename: Renée
authors.initials: R
authors.lastname: Bazin
authors.forename: Frédéric
authors.initials: F
authors.lastname: Calon
mesh_terms: D000818:Animals; D001682:Biological Availability; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000098:blood supply / Q000166:cytology / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D016756:Immunoglobulins, Intravenous
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