Plasma and Brain Concentrations of Doxycycline after Single and Repeated Doses in Wild-Type and APP23 Mice.
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| Abstract |
Repurposing doxycycline for the treatment of amyloidosis has recently been put forward because of the antiaggregating and anti-inflammatory properties of the drug. Most of the investigations of the therapeutic potential of doxycycline for neurodegenerative amyloidosis, e.g., prion and Alzheimer disease (AD), have been carried out in mouse models, but surprisingly no data are available regarding the concentrations reached in the brain after systemic administration. We filled this gap by analyzing the pharmacokinetic profile of doxycycline in plasma and brain after single and repeated intraperitoneal injections of 10 and 100 mg/kg, in wild-type mice and the APP23 mouse model of AD. The main outcomes of our study are: 1) Peak plasma concentrations ranged from 2 to10 μg/ml, superimposable to those in humans; 2) brain-to-plasma ratio was ∼0.2, comparable to the cerebrospinal fluid/serum ratios in humans; 3) brain Cmax 4-6 hours after a single dose was ∼0.5 (10 mg/kg) and ∼5 μM (100 mg/kg). Notably, these concentrations are lower than those required for the drug's antiaggregating properties as observed in cell-free studies, suggesting that other features underlie the positive cognitive effects in AD mice; 4) elimination half-life was shorter than in humans (3-6 vs. 15-30 hours), therefore no significant accumulation was observed in mouse brain following repeated treatments; and 5) there were no differences between doxycycline concentrations in brain areas of age-matched wild-type and APP23 mice. These data are useful for planning preclinical studies with translational validity, and to identify more reliably the mechanism(s) of action underlying the central in vivo effects of doxycycline.
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| Authors | Jacopo Lucchetti, Claudia Fracasso, Claudia Balducci, Alice Passoni, Gianluigi Forloni, Mario Salmona, Marco Gobbi |
| Journal | The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 368 Issue 1 Pg. 32-40 (01 2019) ISSN: 1521-0103 [Electronic] United States |
| PMID | 30396916 (Publication Type: Journal Article) |
| Copyright | Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics. |
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