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E‐ and Z‐10‐hydroxylation of nortriptyline: Relationship to polymorphic debrisoquine hydroxylation
Author(s) -
Mellström B,
Bertilsson L,
Säwe J,
Schulz HU,
Sjöqvist F
Publication year - 1981
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.1981.147
Subject(s) - debrisoquine , hydroxylation , chemistry , urine , nortriptyline , pharmacology , metabolism , pharmacokinetics , metabolite , endocrinology , enzyme , cyp2d6 , biochemistry , medicine , cytochrome p450 , amitriptyline
Eight healthy subjects [who were phenotyped with a debrisoquine (D) hydroxylation test] were selected to cover a wide range in the ratio between D and 4‐hydroxydebrisoquine (4‐OH‐D) in the urine. After a single oral dose of nortriptyline (NT) the metabolic clearance by 10‐hydroxylation in the E‐position, but not in the Z‐position, correlated closely to the metabolic ratio D/4‐0H‐D (r s = ‐0.88, p < 0.01). This indicates that common enzymatic mechanisms are involved in the hydroxylation of D and the E‐ but not the Z‐10‐hydroxylation of NT. Slow hydroxylators of NT and D excreted less 10‐hydroxynortriptyline in urine and had lower plasma clearance of NT than the rapid hydroxylators. The strong correlation (r = 0.96) between the total plasma clearance of NT and the metabolic clearance by E‐10‐hydroxylation shows that this metabolic reaction is important in the disposition of the drug. Clinical Pharmacology and Therapeutics (1981) 30, 189–193; doi: 10.1038/clpt.1981.147