Aging effects on the organic base transporter and stereoselective renal clearance.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Ujhelyi
M R
MR
University of Georgia College of Pharmacy, Augusta, USA.
Bottorff
M B
MB
Schur
M
M
Roll
K
K
Zhang
H
H
Stewart
J
J
Markel
M L
ML
D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics*; D000328:Adult; D000368:Aged; D000375:Aging / Q000378:metabolism*; D000643:Ammonium Chloride / Q000494:pharmacology*; D000963:Antimetabolites / Q000494:pharmacology*; D001692:Biological Transport; D003404:Creatinine / Q000652:urine; D018592:Cross-Over Studies; D004338:Drug Combinations; D005919:Glomerular Filtration Rate; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010869:Pindolol / Q000493:pharmacokinetics*; D013237:Stereoisomerism; D014295:Trimethoprim / Q000494:pharmacology*
D000319:Adrenergic beta-Antagonists; D000963:Antimetabolites; D004338:Drug Combinations; D000643:Ammonium Chloride; D014295:Trimethoprim; D003404:Creatinine; D010869:Pindolol