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Phenotypic consistency in hydroxylation of desmethylimipramine and debrisoquine in healthy subjects and in human liver microsomes
Author(s) -
Spina Edoardo,
Birgersson Carol,
Bahr Christer,
Ericsson Ö,
Mellström Britt,
Steiner Eugen,
Sjöqvist Folke
Publication year - 1984
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.1984.239
Subject(s) - debrisoquine , hydroxylation , microsome , urine , chemistry , medicine , endocrinology , microsoma , cytochrome p450 , urinary system , isozyme , pharmacology , metabolism , cyp2d6 , biology , biochemistry , enzyme
The 2‐hydroxylation of desmethylimipramine (DMI) and the 4‐hydroxylation of debrisoquine (D) were studied in healthy subjects and in human liver microsomes. A single oral dose of DMI (25 mg) was given to 18 healthy subjects previously phenotyped with D (13 rapid and five slow hydroxylators). Urine was collected for 24 hr and DMI and total 2‐hydroxydesmethylimipramine (2‐OH‐DMI) levels were determined by HPLC. The urinary ratio DMI/2‐OH‐DMI correlated strongly (r = 0.92) with the urinary ratio of D to 4‐hydroxydebrisoquine (D/4‐OH‐D). The two hydroxydations were also studied in human liver microsomes from 10 different subjects. Formation rates of the hydroxylated metabolites correlated strongly (r = 0.869). Moreover, D competitively inhibited the 2‐hydroxylation of DMI. These findings suggest that both are hydroxylated by the same cytochrome P‐450 isozyme. Clinical Pharmacology and Therapeutics (1984) 36, 677–682; doi: 10.1038/clpt.1984.239