Ujhelyi M R, Bottorff M B, Schur M, Roll K, Zhang H, Stewart J, Markel M L
University of Georgia College of Pharmacy, Augusta, USA.
Clin Pharmacol Ther. 1997 Aug;62(2):117-28. doi: 10.1016/S0009-9236(97)90059-X.
The organic base transporter is responsible for stereoselective renal excretion. Changes in activity of this system secondary to aging may affect the disposition of an organic base in a stereoselective manner.
Eight young men (age range, 22 to 33 years) and seven elderly men (age range, 62 to 79 years) were given 10 mg pindolol twice daily, pindolol with 200 mg trimethoprim once daily (a known inhibitor of organic base secretion) and pindolol with 1.5 gm ammonium chloride (NH4Cl) four times daily for 3 days on three occasions. On day 4, urine and plasma were collected over 24 hours to determine renal clearance (CLR) values of pindolol isomers.
R(+)-Pindolol CLR values in young versus elderly men were 203 +/- 82 versus 150 +/- 87 ml/min, 128 +/- 51 versus 113 +/- 35 ml/min, and 480 +/- 248 versus 247 +/- 59 ml/min during the control, trimethoprim, and NH4Cl study phases, respectively. S(-)-Pindolol CLR values in young versus elderly were 279 +/- 81 versus 207 +/- 105 ml/min, 178 +/- 70 versus 136 +/- 42 ml/min, and 593 +/- 294 versus 276 +/- 49 ml/min during control, trimethoprim, and NH4Cl phases, respectively. NH4Cl increased R(+)-pindolol CLR by 138% (p < 0.05 versus pindolol alone) in young men, which was significantly greater than that observed in elderly subjects (66%; p < 0.05 versus pindolol alone; p = 0.016 young versus old). NH4Cl affected S(-)-pindolol CLR in a similar manner. Trimethoprim decreased R(+)-pindolol CLR in the young subjects by 37% (p < 0.05 versus pindolol alone), which was similar to that observed in the elderly subjects (26%; p < 0.05 versus pindolol alone; p = 0.94 young versus elderly). Trimethoprim affected S(-)-pindolol CLR in a similar manner. Stereoselective renal excretion of pindolol was unaffected by NH4Cl and trimethoprim, where the R(+)/S(-)-pindolol CLR ratio was unchanged (p = NS) from control in the young and elderly subjects. Comparison of the pindolol CLR isomer ratio between young and elderly groups showed no significant differences. Changes in pindolol clearance values resulted in significant changes in beta-blocking activity, assessed by isoproterenol (INN, isoprenaline) testing.
Trimethoprim and NH4Cl significantly affect pindolol renal and total clearance values. Aging does not alter renal excretion of pindolol except for the magnitude by which renal excretion can be stimulated.
有机碱转运体负责立体选择性肾排泄。衰老继发的该系统活性变化可能以立体选择性方式影响有机碱的处置。
8名年轻男性（年龄范围22至33岁）和7名老年男性（年龄范围62至79岁），分三次连续3天每天两次给予10mg吲哚洛尔，每天一次给予吲哚洛尔加200mg甲氧苄啶（一种已知的有机碱分泌抑制剂），每天四次给予吲哚洛尔加1.5g氯化铵（NH₄Cl）。在第4天，收集24小时的尿液和血浆以测定吲哚洛尔异构体的肾清除率（CLR）值。
在对照、甲氧苄啶和NH₄Cl研究阶段，年轻男性与老年男性相比，R(+)-吲哚洛尔的CLR值分别为203±82 vs
150±87ml/min、128±51 vs 113±35ml/min、480±248 vs 247±59ml/min。在对照、甲氧苄啶和NH₄Cl阶段，年轻男性与老年男性相比，S(-)-吲哚洛尔的CLR值分别为279±81 vs 207±105ml/min、178±70 vs 136±42ml/min、593±294 vs 276±49ml/min。NH₄Cl使年轻男性R(+)-吲哚洛尔的CLR增加138%（与单独的吲哚洛尔相比，p<0.05），这显著大于老年受试者中观察到的增加（66%；与单独的吲哚洛尔相比，p<0.05；年轻与老年相比，p = 0.016）。NH₄Cl以类似方式影响S(-)-吲哚洛尔的CLR。甲氧苄啶使年轻受试者中R(+)-吲哚洛尔的CLR降低37%（与单独的吲哚洛尔相比，p<0.05），这与老年受试者中观察到的降低相似（26%；与单独的吲哚洛尔相比，p<0.05；年轻与老年相比，p = 0.94）。甲氧苄啶以类似方式影响S(-)-吲哚洛尔的CLR。NH₄Cl和甲氧苄啶不影响吲哚洛尔的立体选择性肾排泄，年轻和老年受试者中R(+)/S(-)-吲哚洛尔CLR比值与对照相比无变化（p = 无显著性差异）。年轻组和老年组之间吲哚洛尔CLR异构体比值的比较无显著差异。通过异丙肾上腺素检测评估，吲哚洛尔清除率值的变化导致β受体阻滞活性发生显著变化。
甲氧苄啶和NH₄Cl显著影响吲哚洛尔的肾清除率和总清除率值。衰老除了改变肾排泄受刺激的程度外，不改变吲哚洛尔的肾排泄。
