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Enantioselective amitriptyline metabolism in patients phenotyped for two cytochrome P450 isozymes
Author(s) -
BreyerPfaff Ursula,
Pfandl Brigitte,
Nill Karl,
Nusser Elfriede,
Monney Christian,
JonzierPerey Michele,
Baettig Dominique,
Baumann Pierre
Publication year - 1992
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.1992.155
Subject(s) - mephenytoin , dextromethorphan , chemistry , cyp2d6 , pharmacology , amitriptyline , cytochrome p450 , glucuronide , cyp3a , cyp2c19 , isozyme , pharmacogenetics , urine , metabolism , biochemistry , enzyme , genotype , medicine , gene
In 26 hospitalized patients with depression, a combined pharmacogenetic test with dextromethorphan, a substrate of cytochrome P450IID6, and mephenytoin, the S ‐form of which is hydroxylated by a P450IIC isozyme, was carried out before amitriptyline therapy. Metabolites were determined in 24‐hour urine samples collected on treatment day 8, and the contributions of individual compounds, including the four isomers of 10‐hydroxyamitriptyline and 10‐hydroxynortriptyline, to total excretion were calculated. Formation of (−)‐E‐10‐hydroxyamitriptyline and (−)‐E‐10‐hydroxynortriptyline apparently depends on the activity of cytochrome P450IID6 because negative correlations existed between the log metabolic ratio of dextromethorphan and the relative quantities of these enantiomers. In contrast, correlations were positive for nortriptyline, (+)‐E‐10‐hydroxynortriptyline, (−)‐Z‐10‐hydroxynortriptyline, and (+)‐Z‐10‐hydroxynortriptyline. The mephenytoin hydroxylase seems to participate in side‐chain demethylation to the secondary and primary amines, because the log metabolic ratio of mephenytoin correlated negatively with the relative quantity of E‐10‐hydroxydidesmethylamitriptyline and positively with that of amitriptyline and its N ‐glucuronide. Clinical Pharmacology and Therapeutics (1992) 52, 350–358; doi: 10.1038/clpt.1992.155