RT Journal Article
SR Electronic
T1 Plasma and brain concentrations of doxycycline after single and repeated doses in wild-type and APP23 mice
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.118.252064
DO 10.1124/jpet.118.252064
A1 Jacopo Lucchetti
A1 Claudia Fracasso
A1 Claudia Balducci
A1 Alice Passoni
A1 Gianluigi Forloni
A1 Mario Salmona
A1 Marco Gobbi
YR 2018
UL http://jpet.aspetjournals.org/content/early/2018/11/05/jpet.118.252064.abstract
AB Repurposing doxycycline for the treatment of amyloidosis has recently been put forward based on the anti-aggregating and anti-inflammatory properties of this drug. Most of the investigations on the therapeutic potential of doxycycline for neurodegenerative amyloidosis, e.g. prion and Alzheimer disease (AD), are carried out in mouse models but, surprisingly, no data are available as regards the concentrations reached in the brain after systemic administration. We filled this gap by analysing 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 the AD. The main outcomes of our study are: i) peak plasma concentrations ranged 2-10 μg/mL, superimposable to those in humans; ii) brain-to-plasma ratio was ~0.2, comparable to the CSF/serum ratios in humans; iii) brain Cmax, 4-6 h after a single dose, was ~0.5 μM (10 mg/kg) and ~5 μM (100 mg/kg). Notably, these concentrations are lower than those required for the drug's anti-aggregating properties as observed in cell-free studies, suggesting that other features underlie the positive cognitive effects in AD mice; iv) elimination half-life was shorter than in humans (3-6h vs 15-30h), therefore no significant accumulation was observed in mouse brain following repeated treatments; v) 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 the mechanism(s) of action underlying the central in vivo effects of doxycycline more reliably.