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IN VITRO AND IN VIVO INHIBITORY EFFECT OF STIRIPENTOL ON CLOBAZAM METABOLISM

Department of Pharmacology, Université Paris-Descartes, Faculté de Médecine, Groupe Hospitalier Cochin St. Vincent de Paul (C.G., J.-M.T., E.R., G.P.), Neurologie et Métabolisme, Hôpital Necker (C.C.), and Assistance Publique-Hopitaux de Paris, Paris, France; Biocodex, Gentilly, France (J.V.); and Ecole Pratique des Hautes Etudes, Paris, France (A.T.)

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 IC₅₀ 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 µM and IC₅₀ = 1.58 µM [95% confidence interval (CI95%) = 1.20–2.08] and 3.29 µM (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 µM and IC₅₀ = 0.276 µM (CI95% = 0.206–0.371)]. The inhibitory effect of STP on CLB demethylation by CYP3A4 was much weaker than that of ketoconazole [IC₅₀ = 0.023 µM (CI95% = 0.016–0.033)], whereas its effect on NCLB hydroxylation by CYP2C19 was much higher than that of omeprazole [IC₅₀ = 2.99 µM (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.