Rhesus monkey cerebrospinal fluid amine metabolite changes following treatment with the reversible monoamine oxidase type-A inhibitor cimoxatone.
The effects of cimoxatone, a reversible inhibitor of monoamine oxidase type A (MAO-A), on the deaminated metabolites of norepinephrine, dopamine, and serotonin were examined in continuously collected rhesus monkey cerebrospinal fluid (CSF). Cimoxatone, 0.5-8 mg/kg given PO, produced dose-proportionate reductions of 24-h mean CSF 3-methoxy, 4-hydroxy phenylglycol (MHPG) concentrations of 21%-52%. Homovanillic acid (HVA) concentrations also decreased 27%-55%, while CSF 5-hydroxyindoleacetic acid (5-HIAA) decreases were somewhat smaller (7%-32% from baseline). All three metabolite concentrations reached a nadir approximately 6-10 h after drug administration, and required over 40 h to gradually return towards baseline following drug discontinuation. HVA concentration reductions in particular persisted during the entire 24-h period following treatment and were the slowest to return to baseline values. CSF concentrations of cimoxatone and its MAO-inhibiting O-demethyl metabolite showed a parallel time course, peaking 6-10 h after treatment and persisting for up to 24 h in the case of cimoxatone and over 48 h for its metabolite. Single simultaneous time point determinations revealed 10-to 20-fold lower concentrations of cimoxatone and its metabolite in CSF compared to plasma 2 h after treatment. MAO-B activity in platelet-rich plasma was not inhibited by 8 mg/kg cimoxatone, indicating that this drug maintains MAO-A selectivity in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)
N A
NA
Garrick
T
T
Seppala
M
M
Linnoila
D L
DL
Murphy
D000818:Animals; D001679:Biogenic Amines / Q000134:cerebrospinal fluid*; D004305:Dose-Response Relationship, Drug; D006719:Homovanillic Acid / Q000134:cerebrospinal fluid; D006897:Hydroxyindoleacetic Acid / Q000134:cerebrospinal fluid; D008253:Macaca mulatta; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000134:cerebrospinal fluid; D008996:Monoamine Oxidase Inhibitors / Q000134:cerebrospinal fluid / Q000494:pharmacology*; D010080:Oxazoles / Q000134:cerebrospinal fluid / Q000494:pharmacology*; D023303:Oxazolidinones
D001679:Biogenic Amines; D008996:Monoamine Oxidase Inhibitors; D010080:Oxazoles; D023303:Oxazolidinones; D008734:Methoxyhydroxyphenylglycol; D006897:Hydroxyindoleacetic Acid; C038383:MD 770222; C026234:cimoxatone; D006719:Homovanillic Acid