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Age-associated stereoselective alterations in hexobarbital metabolism
M H Chandler1, S R Scott, R A Blouin
1Drug Product Evaluation Unit, University of Kentucky College of Pharmacy, Lexington 40536-0082.
Clinical Pharmacology and Therapeutics
|April 1, 1988
Summary
Elderly individuals show a significantly slower metabolism of l-hexobarbital compared to younger adults, impacting drug disposition. This age-related difference in stereoselective drug metabolism was not previously reported for any racemic drug.
Area of Science:
- Pharmacology
- Gerontology
- Drug Metabolism
Background:
- Age significantly influences drug pharmacokinetics and pharmacodynamics.
- Stereoselective drug disposition, where different enantiomers of a drug are processed differently, is crucial for understanding drug efficacy and safety.
- Hexobarbital serves as a model racemic drug to investigate age-related changes in stereoselective metabolism.
Purpose of the Study:
- To investigate the influence of age on the stereoselective disposition of hexobarbital enantiomers.
- To compare the oral clearance of d- and l-hexobarbital in young versus elderly healthy male volunteers.
- To determine if age affects the enantiomeric oral clearance ratio of hexobarbital.
Main Methods:
- A clinical investigation involving 10 young and 10 elderly healthy male volunteers.
- Administration of hexobarbital as a model marker drug.
- Measurement and comparison of oral clearance for both d- and l-hexobarbital enantiomers between the two age groups.
Main Results:
- Oral clearance of d-hexobarbital did not differ significantly between young and elderly subjects.
- Oral clearance of l-hexobarbital was approximately twofold greater in young subjects compared to elderly subjects (P < 0.05).
- The enantiomeric oral clearance ratio was significantly greater in young subjects than in elderly subjects (P < 0.01).
Conclusions:
- This study demonstrates an age-related preferential decline in the metabolism of l-hexobarbital, a finding not previously reported for any racemic drug in humans or animals.
- Age significantly impacts the stereoselective disposition of hexobarbital, with elderly individuals exhibiting reduced clearance of the l-enantiomer.
- Despite altered stereoselective metabolism, no significant difference in the pharmacologic response to hexobarbital was observed between young and elderly groups.