Ex vivo inhibition of rat brain cytochrome P-450 activity by stiripentol.
Stiripentol is an anti-epileptic drug of novel structure with previously demonstrated strong in vitro inhibitory activity on rat cerebral cytochrome P-450 mediated naphthalene hydroxylation [6]. When administered to rats as a single i.p. dose, the drug is presently shown to have the same in vitro effect. Maximal inhibition is seen 2 hr after administration, but at this time the brain concentrations of intact drug, although peaking, appear too low (ca. 11 micrograms/g tissue) to account for the intensity of the effect seen in vitro. This suggests in vivo activation to a metabolic intermediate forming a complex with cerebral cytochrome P-450, which 2 hr after dosing is fully insensitive to stiripentol added to incubates. Restoration of enzymic activity and of sensitivity to added stiripentol occurs progressively and is practically complete 24 hr after dosing.
Mesnil
M
M
School of Pharmacy, University of Lausanne, Switzerland.
Testa
B
B
Jenner
P
P
D000818:Animals; D001921:Brain / Q000201:enzymology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D004148:Dioxolanes / Q000378:metabolism / Q000494:pharmacology*; D004149:Dioxoles / Q000494:pharmacology*; D008297:Male; D009281:Naphthalenes / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains
D065607:Cytochrome P-450 Enzyme Inhibitors; D004148:Dioxolanes; D004149:Dioxoles; D009281:Naphthalenes; C031721:naphthalene; C021092:stiripentol