E- and Z-10-hydroxylation of nortriptyline: relationship to polymorphic debrisoquine hydroxylation

Abstract

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-OH-D (rs = -0.88, p less than 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.