Schwartz J B, Capili H, Wainer I W
Department of Medicine, University of California, San Francisco.
Clin Pharmacol Ther. 1994 Oct;56(4):368-76. doi: 10.1038/clpt.1994.151.
Aging decreases elimination of racemic verapamil but reports vary regarding effects of aging on clearance of individual verapamil enantiomers. To determine effects of aging on elimination of S- and R-verapamil, racemic verapamil was infused to steady-state concentrations of approximately 30, 60, and 120 ng/ml in 27 healthy subjects ranging in age from 23 to 81 years (young, 20 to 39 years; middle aged, 40 to 59 years; old, 60 to 81 years), and enantiomer concentrations were measured at each steady-state and after infusions. S-Verapamil clearance was greater than R-verapamil clearance in all age groups (p < 0.001), and aging decreased S-verapamil (p < 0.05) and R-verapamil (p < 0.008) clearance (average +/- SD, S-verapamil clearance was 14.3 +/- 4.7, 13.4 +/- 5.2, and 11.7 +/- 5.2 ml/min/kg; R-verapamil clearance was 6.5 +/- 3.3, 5.6 +/- 2.8, and 4.5 +/- 1.6 ml/min/kg in young, middle-aged, and older subjects, respectively). Enantiomer clearance was not effected by verapamil concentration. A trend toward an age effect on elimination half-lives was seen (S-verapamil half-life, 281 +/- 116 versus 234 +/- 89 minutes in elderly versus young; R-verapamil half-life, 253 +/- 56 versus 199 +/- 58 minutes in elderly versus young, p = 0.08). R- but not S-verapamil clearance during multistage infusions of racemic verapamil was lower than previously reported clearance after single intravenous enantiomer doses (p < 0.0001). In summary, aging decreases clearance of both S- and R-verapamil during steady-state intravenous dosing of racemic verapamil with preserved stereoselective clearance of verapamil with aging.
衰老会降低外消旋维拉帕米的清除率，但关于衰老对外消旋维拉帕米各对映体清除率的影响，报告结果不一。为了确定衰老对S-和R-维拉帕米清除率的影响，对27名年龄在23至81岁之间的健康受试者（年轻组，20至39岁；中年组，40至59岁；老年组，60至81岁）静脉输注外消旋维拉帕米，使其稳态浓度分别达到约30、60和120 ng/ml，并在每个稳态浓度及输注后测量对映体浓度。在所有年龄组中，S-维拉帕米的清除率均高于R-维拉帕米（p < 0.001），并且衰老会降低S-维拉帕米（p < 0.05）和R-维拉帕米（p < 0.008）的清除率（平均值±标准差，年轻、中年和老年受试者的S-维拉帕米清除率分别为14.3±4.7、13.4±5.2和11.7±5.2 ml/min/kg；R-维拉帕米清除率分别为6.5±3.3、5.6±2.8和4.5±1.6 ml/min/kg）。对映体清除率不受维拉帕米浓度影响。观察到清除半衰期存在年龄效应趋势（老年组与年轻组相比，S-维拉帕米半衰期为281±116分钟对234±89分钟；R-维拉帕米半衰期为253±56分钟对199±58分钟，p = 0.08）。在对外消旋维拉帕米进行多阶段输注期间，R-维拉帕米的清除率低于先前报道的单剂量静脉注射对映体后的清除率（p < 0.0001），而S-维拉帕米则不然。总之，在对外消旋维拉帕米进行稳态静脉给药时，衰老会降低S-和R-维拉帕米的清除率，且随着衰老，维拉帕米的立体选择性清除率保持不变。
