Verapamil metabolite exposure in older and younger men during steady-stateoral verapamil administration

To determine the effect of age on exposure to the circulating major verapam il metabolites norverapamil, N-dealkylverapamil (D-617), and N-dealkylnorve rapamil (D-620), plasma concentrations of verapamil and the three metabolit es 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 (ag ed 65-75 years) and 8 younger (20-28 years) healthy male volunteers. Area u nder the plasma concentration time curve (AUC) was greater for verapamil (m ean +/- 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 +/- 77 2 versus 1894 +/- 418 ng/ml.h(-1); not significantly different (NS)] and N- dealkylnorverapamil (897 +/- 366 versus 757 +/- 104 ng/ml.h(-1); NS) in old er as compared with young subjects. These data indicate that impaired verap amil oral clearance previously described in older men does not result in de creased exposure to the formed major metabolites, rather there is increased exposure to norverapamil and the same or a trend toward greater exposure t o D-617 as well. This suggests that in addition to the impaired clearance m echanisms for verapamil, which are thought to be primarily mediated by CYP3 A, biotransformation processes distal to the formation of norverapamil and D-617 are impaired as well.