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Effect of Aging on the Pharmacokinetics of Acebutolol Enantiomers
Author(s) -
PiquetteMiller Micheline,
Foster Robert T.,
Kappagoda C. Tissa,
Jamali Fakhreddin
Publication year - 1992
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/j.1552-4604.1992.tb03820.x
Subject(s) - pharmacokinetics , enantiomer , acebutolol , chemistry , metabolite , urine , pharmacology , stereoselectivity , creatinine , excretion , endocrinology , renal function , renal physiology , medicine , stereochemistry , biochemistry , blood pressure , catalysis
Acebutolol (AC) is a chiral β‐blocker that is metabolized to an equipotent chiral metabolite, diacetolol (DC). A stereoselective disposition of AC and DC enantiomers has recently been reported in young healthy subjects. As many physiologic properties affecting drug disposition are progressively altered with increasing age, the effect of aging on the pharmacokinetics of AC and DC enantiomers were investigated in nine subjects ranging from 60 to 75 years after administration of an oral 200‐mg dose of racemic AC. Increasing age resulted in a significant prolongation of the elimination t1/2s of R‐ (r=0.913) and S‐DC (r=0.811). Also, the S:R ratios of AC urinary excretion (ΣXu) of enantiomers was significantly correlated with age (r=0.677). Contribution of declining renal junction to age‐associated pharmacokinetics changes was subsequently examined. Renal clearance and cumulative urinary excretion of both AC and DC enantiomers were positively correlated with creatinine clearance. In addition, declining creatinine clearance was associated with a subsequent decline in the enantiomer S:R ratio of AC in plasma (AUC S:R, r=0.807) and urine (ΣXu S;R r=0.807). Similarly, a progressive decline in the S:R ratio of DC collected in urine was evident (r=0.689). Age‐related changes in the enantiomers ratios may suggest that an active stereoselective pathway such as renal tubular secretion or nonrenal excretion may be affected in the elderly.