TY - JOUR
T1 - In vitro inhibition of tricyclic antidepressants (TCAs) on phenytoin P-hydroxylation
T2 - Involvement of CYP2C9 and CYP2C19
AU - Park, J. Y.
AU - Shon, J. H.
AU - Kim, M. J.
AU - Cha, I. J.
AU - Flockhart, D. A.
AU - Shin, J. G.
PY - 2001
Y1 - 2001
N2 - Two case reports have been described that imipramine, a TCA, increased serum concentration of coadministered phenytoin (PHT), a substrate of CYP2C9 and CYP2C19. To understand the mechanism of this interaction, we assessed the in vitro inhibition of TCAs (imipramine, desipramine, amitriptyline, and nortriptyline) on phenytoin p-hydroxylation and probe metabolic pathways of each CYP isoform using the incubation study of human liver microsomes and cDNA-expressed cytochrome P450s. Imipramine and amitriptyline competitively and strongly inhibited PHT p-hydroxylation with the estimated Ki of 6.5±2.6 μM and 2.2±0.2 μM, respectively. The inhibitory effects of desipramine and nortriptyline were weaker than those of their parent drugs (up to 11-19% of control at highest concentration). All TCAs strongly inhibited CYP2D6-catalyzed dextromethorphan O-demethylation (Ki=8-30 (J-M). Imipramine and amitriptyline slightly inhibited CYP2C9-catalyzed tolbutamide 4-methylhydroxylation and CYP2C19-catalyzed S-mephenytoin 4-hydroxylation (<25%), but no inhibitions were on CYP1A2- and CYP3A4-catalyzed reactions. TCAs inhibited the formation of p-hydroxyphenytoin in cDNA-expressed CYP2C9 and CYP2C19 (20-70% of control). In conclusion, TCAs appear to have a potential to increase the serum concentration of PHT coadministered through the inhibition of CYP2C9- and CYP2C19-catalyzed phenytoin p-hydroxylation.
AB - Two case reports have been described that imipramine, a TCA, increased serum concentration of coadministered phenytoin (PHT), a substrate of CYP2C9 and CYP2C19. To understand the mechanism of this interaction, we assessed the in vitro inhibition of TCAs (imipramine, desipramine, amitriptyline, and nortriptyline) on phenytoin p-hydroxylation and probe metabolic pathways of each CYP isoform using the incubation study of human liver microsomes and cDNA-expressed cytochrome P450s. Imipramine and amitriptyline competitively and strongly inhibited PHT p-hydroxylation with the estimated Ki of 6.5±2.6 μM and 2.2±0.2 μM, respectively. The inhibitory effects of desipramine and nortriptyline were weaker than those of their parent drugs (up to 11-19% of control at highest concentration). All TCAs strongly inhibited CYP2D6-catalyzed dextromethorphan O-demethylation (Ki=8-30 (J-M). Imipramine and amitriptyline slightly inhibited CYP2C9-catalyzed tolbutamide 4-methylhydroxylation and CYP2C19-catalyzed S-mephenytoin 4-hydroxylation (<25%), but no inhibitions were on CYP1A2- and CYP3A4-catalyzed reactions. TCAs inhibited the formation of p-hydroxyphenytoin in cDNA-expressed CYP2C9 and CYP2C19 (20-70% of control). In conclusion, TCAs appear to have a potential to increase the serum concentration of PHT coadministered through the inhibition of CYP2C9- and CYP2C19-catalyzed phenytoin p-hydroxylation.
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M3 - Article
AN - SCOPUS:33748970641
VL - 69
SP - P78
JO - Clinical Pharmacology and Therapeutics
JF - Clinical Pharmacology and Therapeutics
SN - 0009-9236
IS - 2
ER -