Brain Uptake of Tetrahydrohyperforin and Potential Metabolites after Repeated Dosing in Mice.
Tetrahydrohyperforin (IDN-5706) is a semisynthetic derivative of hyperforin, one of the main active components of Hypericum perforatum extracts. It showed remarkable positive effects on memory and cognitive performances in wild-type mice and in a transgenic mouse model of Alzheimer's disease, but little was known about the concentrations it can reach in the brain. The investigations reported herein show that repeated treatment of mice with tetrahydrohyperforin (20 mg/kg intraperitoneally, twice daily for 4 days and once on the fifth day) results in measurable concentrations in the brain, up to 367 ng/g brain (∼700 nM) 6 h after the last dose; these concentrations have significant effects on synaptic function in hippocampal slices. The other main finding was the identification and semiquantitative analysis of tetrahydrohyperforin metabolites. In plasma, three hydroxylated/dehydrogenated metabolites were the largest (M1-3) and were also formed in vitro on incubation of tetrahydrohyperforin with mouse liver microsomes; the fourth metabolite in abundance was a hydroxylated/deisopropylated derivative (M13), which was not predicted in vitro. These metabolites were all detected in the brain, with peak areas from 10% (M1) to ∼1.5% (M2, M3, and M13) of the parent compound. In summary, repeated treatment of mice with tetrahydrohyperforin gave brain concentrations that might well underlie its central pharmacological effects. We also provide the first metabolic profile of this compound.
IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri" , 20156 Milan, Italy.
Claudia
C
Fracasso
IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri" , 20156 Milan, Italy.
Renzo
R
Bagnati
IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri" , 20156 Milan, Italy.
Alice
A
Passoni
IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri" , 20156 Milan, Italy.
Giovanna
G
Guiso
IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri" , 20156 Milan, Italy.
Lavinia
L
Cantoni
Indena S.p.A. , 20139 Milan, Italy.
Antonella
A
Riva
Indena S.p.A. , 20139 Milan, Italy.
Paolo
P
Morazzoni
IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri" , 20156 Milan, Italy.
Marco
M
Gobbi
D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D001921:Brain / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism; D020902:Hypericum / Q000737:chemistry*; D051379:Mice; D008862:Microsomes, Liver; D015394:Molecular Structure; D010696:Phloroglucinol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D013729:Terpenes / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*
D013729:Terpenes; D010696:Phloroglucinol; C001654:hyperforin