TY - JOUR T1 - Verapamil Metabolite Exposure in Older and Younger Men during Steady-State Oral Verapamil Administration JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 760 LP - 765 VL - 28 IS - 7 AU - Darrell R. Abernethy AU - Irving W. Wainer AU - Ana Isabel Anacleto Y1 - 2000/07/01 UR - http://dmd.aspetjournals.org/content/28/7/760.abstract N2 - To determine the effect of age on exposure to the circulating major verapamil metabolites norverapamil, N-dealkylverapamil (D-617), and N-dealkylnorverapamil (D-620), plasma concentrations of verapamil and the three metabolites were determined during the last dose interval of a 14-day administration period of 240 mg of sustained release verapamil once daily in 11 older (aged 65–75 years) and 8 younger (20–28 years) healthy male volunteers. Area under the plasma concentration time curve (AUC) was greater for verapamil (mean ± S.D.) (2815 ± 733 older versus 1639 ± 466 ng/ml·h−1 young;P < .0007) and norverapamil (2927 ± 655 versus 2143 ± 471 ng/ml·h−1; P< .007); however, it was not significantly different for D-617 [2386 ± 772 versus 1894 ± 418 ng/ml·h−1; not significantly different (NS)] andN-dealkylnorverapamil (897 ± 366 versus 757 ± 104 ng/ml·h−1; NS) in older as compared with young subjects. These data indicate that impaired verapamil oral clearance previously described in older men does not result in decreased exposure to the formed major metabolites, rather there is increased exposure to norverapamil and the same or a trend toward greater exposure to D-617 as well. This suggests that in addition to the impaired clearance mechanisms for verapamil, which are thought to be primarily mediated by CYP3A, biotransformation processes distal to the formation of norverapamil and D-617 are impaired as well. U.S. Government ER -