Synthesis and identification of the N-glucuronides of norgallopamil and norverapamil, unusual metabolites of gallopamil and verapamil.

N-Glucuronides of norgallopamil and norverapamil were found as biliary metabolites after administering the corresponding tertiary amines, gallopamil and verapamil, to rats. The structures of these unusual metabolites were established by comparison with spectral data of synthesized authentic standards and by enzymic hydrolysis of the conjugates. The N-glucuronide standards were synthesized by coupling the secondary amines to either glucuronic acid or to methyl tetra-O-acetyl-beta-D-glucopyranuronate. On i.p. dosing of rats with gallopamil or verapamil, 13 and 2% of the dose, respectively, appeared in the bile as the N-glucuronide of the secondary amine metabolite over an 8-hr period. Administration of norgallopamil resulted in approximately 25% of the dose being excreted as N-glucuronide conjugate in the bile. Substantially more of the S- than R-enantiomer of both gallopamil and verapamil was converted to the corresponding secondary amine N-glucuronide. The observed high S/R ratios suggest enantio-selectivity in this pathway could contribute to the observed stereoselectivity in other routes of metabolism of the parent tertiary amines.