Enantioselectivity of 4‐hydroxylation in extensive and poor metabolizers of debrisoquine.

Abstract

Debrisoquine (DQ) has no chiral centre, but hydroxylation in position 4 leads to formation of an asymmetric carbon centre with two possible enantiomers, their absolute configuration being R(‐) and S(+)‐4‐ hydroxydebrisoquine (4‐OHDQ). Since the absolute stereochemistry of the 4‐hydroxylation of DQ in man is unknown, the enantioselectivity of this process was studied in panels of extensive (EM) and poor metabolizers (PM) of DQ. In EM subjects 4‐hydroxylation of DQ leads almost exclusively to the formation of S(+)‐4‐OHDQ. In contrast, PM subjects were not only characterized by a decreased total 4‐OHDQ formation but also a marked loss of enantioselectivity in product formation. Between 5 to 36% of total 4‐OHDQ was excreted as R(‐)‐4‐OHDQ. 1988 The British Pharmacological Society