This proposal will investigate the effect of age on propranolol steroselective disposition and response in man. Beta-receptors in the elderly appear to have a diminished in-vivo affinity for propranolol. Evidence for a change in propranolol binding to these receptors, however, has been based upon the relationship between total racemic drug levels and effect. Little is known about the influence of age on the steroselective disposition of propranolol, even though changes in its enantiomeric composition in-vivo could alter its response and influence conclusions about the diminished affinity of beta-receptors for propranolol in the aged. Recent evidence has shown the steroselective disposition of hexobarbital is altered by age in man and the possibility exists that other racemic drugs, like propranolol, may also be affected. More detailed cross-sectional studies of age related effects on propranolol steroselective disposition and in-vivo binding to beta- receptors in man are proposed which will define both the extent and rate change in these parameters with age. The specific hypothesis to be tested is: An age associated alteration in the enantiomeric disposition of propranolol occurs in man which contributes to the apparent altered sensitivity of the elderly to this drug. The testing of this hypothesis will involve a multidisciplinary team with expertise in analytical methods, protein binding and clinical procedures. This research should provide valuable basic information by delineating the influence of age on the steroselective disposition and response to propranolol.
