Brain uptake and distribution of the potential memory enhancer CL 275,838 and its main metabolites in rats: relationship between brain concentrations and in vitro potencies on neurotransmitter mechanisms.
The kinetics, brain uptake and distribution of CL 275,838, a potential memory enhancer, and its main metabolites (II and IV) were evaluated in rats after intraperitoneal doses of 5, 10 and 20 mg/kg. Brain maximum concentrations (Cmax) of the three compounds after pharmacologically active doses were then related to the in vitro concentrations affecting some monoaminergic and amino acid receptor sites to examine the relative importance of these neurotransmitter systems in the pharmacological actions of CL 275,838. After 10 mg/kg CL 275,838, the unchanged compound rapidly entered the brain and distributed almost uniformly in various regions inside the blood-brain barrier. Its disappearance from brain and plasma was almost parallel with a comparable elimination half-life (t 1/2) of about 2 h. Metabolite II entered the brain and equilibrated with plasma more slowly than the parent compound, achieving mean Cmax (0.2 microM) within 3 h of dosing. Metabolite IV was rapidly detected in rat brain but hardly amounted to 10% (0.1 microM) of the parent compound Cmax (1 microM). There was a linear relationship between dose and plasma and brain concentrations of the three compounds up to 20 mg/kg CL 275,838. At micromolar concentrations the parent compound had affinity for serotonin (5-HT) uptake sites, 5-HT2 and dopamine (DA2) receptors. Only at much higher concentrations than those achieved in vivo after pharmacologically active doses did it increase the binding of 3H-glutamate to NMDA (N-methyl-D-aspartate) receptors. Metabolite II has a similar neurochemical profile.(ABSTRACT TRUNCATED AT 250 WORDS)
Caccia
S
S
Istituto di Ricerche Farmacologiche, Mario Negri, Milan, Italy.
Confalonieri
S
S
Guiso
G
G
Bernasconi
P
P
Cagnotto
A
A
Skorupska
M
M
Mennini
T
T
D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism*; D001711:Biotransformation; D001921:Brain / Q000378:metabolism*; D006207:Half-Life; D066298:In Vitro Techniques; D008297:Male; D008568:Memory / Q000187:drug effects*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010879:Piperazines / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011720:Pyrazoles / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011743:Pyrimidines / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism*
D015306:Biogenic Monoamines; D018377:Neurotransmitter Agents; D010879:Piperazines; D011720:Pyrazoles; D011743:Pyrimidines; D011963:Receptors, GABA-A; D017981:Receptors, Neurotransmitter; C074871:CL 275838