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Aging effects on the organic base transporter and stereoselective renal clearance
Author(s) -
Ujhelyi Michael R.,
Bottorff Michael B.,
Schur Michael,
Roll Kevin,
Zhang Hailang,
Stewart James,
Markel Michael L.
Publication year - 1997
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/s0009-9236(97)90059-x
Subject(s) - transporter , stereoselectivity , pharmacology , chemistry , base (topology) , organic cation transport proteins , medicine , biochemistry , mathematics , gene , catalysis , mathematical analysis
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 (NH 4 Cl) four times daily for 3 days on three occasions. On day 4, urine and plasma were collected over 24 hours to determine renal clearance (CL R ) values of pindolol isomers. Results: R (+)‐Pindolol CL R 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 NH 4 Cl study phases, respectively. S (‐)‐Pindolol CL R 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 NH 4 Cl phases, respectively. NH 4 Cl increased R (+)‐pindolol CL R 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). NH 4 Cl affected S (‐)‐pindolol CL R in a similar manner. Trimethoprim decreased R (+)‐pindolol CL R 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 CL R in a similar manner. Stereoselective renal excretion of pindolol was unaffected by NH 4 Cl and trimethoprim, where the R (+)/ S (‐)‐pindolol CL R ratio was unchanged ( p = NS ) from control in the young and elderly subjects. Comparison of the pindolol CL R isomer ratio between young and elderly groups showed no significant differences. Changes in pindolol clearance values resulted in significant changes in β‐blocking activity, assessed by isoproterenol (INN, isoprenaline) testing. Conclusions Trimethoprim and NH 4 Cl 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. Clinical Pharmacology & Therapeutics (1997) 62 , 117–128; doi: