In vitro and in vivo inhibitory effect of stiripentol on clobazam metabolism.
A metabolic interaction between stiripentol (STP), an anticonvulsant agent that inhibits the activity of several cytochromes P450 (P450s), and clobazam (CLB), a 1,5-benzodiazepine, used in association with STP in severe myoclonic epilepsy in infancy was observed in vivo. This interaction was characterized in vitro using cDNA-expressed CYP3A4 and CYP2C19 (main P450 involved in CLB metabolism) to calculate K(i) and IC(50) of stiripentol in comparison with ketoconazole (CYP3A4 inhibitor) and omeprazole (CYP2C19 inhibitor). STP inhibited N-demethylation of CLB to N-desmethylclobazam (NCLB) mediated by CYP3A4 (noncompetitively) and CYP2C19 (competitively) with K(i) = 1.59 +/- 0.07 and 0.516 +/- 0.065 microM and IC(50) = 1.58 microM [95% confidence interval (CI95%) = 1.20-2.08] and 3.29 microM (CI95% = 1.87-5.79), respectively. STP inhibited also more strongly the 4'-hydroxylation of NCLB to 4'-hydroxy-N-desmethylclobazam by CYP2C19 [competitive interaction with K(i) = 0.139 +/- 0.025 microM and IC(50) = 0.276 microM (CI95% = 0.206-0.371)]. The inhibitory effect of STP on CLB demethylation by CYP3A4 was much weaker than that of ketoconazole [IC(50) = 0.023 microM (CI95% = 0.016-0.033)], whereas its effect on NCLB hydroxylation by CYP2C19 was much higher than that of omeprazole [IC(50) = 2.99 microM (CI95% = 2.11-4.24)]. The major in vitro inhibitory effect of STP on CLB metabolism and mostly on NCLB biotransformation is consistent with the changes in vivo in CLB and NCLB plasma concentrations in children treated by the association CLB/STP.
Giraud
Carole
C
Department of Pharmacology, Université Paris-Descartes, Faculté de Médecine, Groupe Hospitalier Cochin St. Vincent de Paul, Paris, France.
Treluyer
Jean-Marc
JM
Rey
Elisabeth
E
Chiron
Catherine
C
Vincent
Jean
J
Pons
Gérard
G
Tran
Agnès
A
D000927:Anticonvulsants / Q000378:metabolism* / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001569:Benzodiazepines / Q000378:metabolism*; D002986:Clinical Trials as Topic; D000078306:Clobazam; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004148:Dioxolanes / Q000494:pharmacology*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007654:Ketoconazole / Q000494:pharmacology; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009853:Omeprazole / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism
D000927:Anticonvulsants; D065607:Cytochrome P-450 Enzyme Inhibitors; D004148:Dioxolanes; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D001569:Benzodiazepines; D000078306:Clobazam; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D009853:Omeprazole; C021092:stiripentol; D007654:Ketoconazole