Brain extraction of 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]pyridinium ion (HPP+), a neurotoxic metabolite of haloperidol: studies using [3H]HPP+.
Tritium-labeled 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]pyridinium ion (HPP+) was synthesized enzymatically from [3H]haloperidol using rat liver microsomal preparations, and using prepared [3H]HPP+, the passage of HPP+ into the brain was investigated. Consequently, HPP+ showed a moderate brain uptake index, indicating that it is able to permeate the blood-brain barrier. Furthermore, HPP+ was detected in murine brains after being intravenously injected. These results suggested that HPP+, produced mainly in the liver, is taken up into the brain and induces damage to brain dopaminergic neurons.
Kawashima
Hidekazu
H
Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Japan.
Iida
Yasuhiko
Y
Kitamura
Youji
Y
Kiyono
Yasushi
Y
Magata
Yasuhiro
Y
Saji
Hideo
H
D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D006220:Haloperidol / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity*; D008297:Male; D051379:Mice; D011726:Pyridinium Compounds / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar
D011726:Pyridinium Compounds; C085216:N-(4'-fluorobutyrophenone)-4-(4-chlorophenyl)pyridinium; D006220:Haloperidol