Lack of effect of ageing on the stereochemical disposition of propranolol.

Hh, Zhou; Whelan, E.; Wood, A. J. J.

doi:10.1111/j.1365-2125.1992.tb04012.x

Cited by 17 publications

(11 citation statements)

References 17 publications

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“…Such is the case with calcium antagonists [69]. Thiazide diuretics, ACE inhibitors and some ß-blockers in the elderly should be adjusted according to renal function rather than age [70,71]. These features are summarized in table 1.…”

Section: Antihypertensive Drugsmentioning

confidence: 99%

Aging Liver

Anantharaju¹,

Feller²,

Chedid³

2002

Gerontology

167

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Aging is characterized by a progressive decline of cellular functions. The aging liver appears to preserve its function relatively well. Aging is associated in human liver with morphological changes such as decrease in size attributable to decreased hepatic blood flow. Ultrastructural analysis of the human liver has revealed that the integrity of mitochondria and enzymatic activity remain mostly unchanged with aging. Reactive oxygen species (ROS) are involved in the aging process and result mainly from nonenzymatic processes in the liver. Endogenous free radicals are generated within mitochondria and suspected to cause severe injury to mitochondrial DNA. This damaged DNA accumulates with aging. In addition, polyunsaturated fatty acids, highly sensitive to ROS, decrease in liver mitochondria from human centenarians, a feature acquired during evolution as a protective mechanism to favor longevity. Diet is considered the main environmental factor having effect on lifespan. It has a major impact on aging liver, the central metabolic organ of the body. The ubiquitin proteolytic pathway in the liver serves to destroy many proteins, among them p21 which is encoded by abundant mRNA in senescent cells, can inhibit cell proliferation and favors DNA repair. Drug therapy in the elderly may be complicated by several factors such as decline in body weight, renal function, liver mass and hepatic blood flow, making adverse drug reactions more frequent. Hepatic drug metabolism is mainly mediated by the cytochrome P₄₅₀system and drug interactions in the elderly are likely related to the progressive decline of this system after the fifth decade of life and another decrease in individuals aged >70. Antihypertensive therapy in the elderly depends upon either hepatic or renal function and should be adjusted accordingly. Finally, telomerases are the biological clocks of replicative lifespan. Shortening of telomeric ends of chromosomes correlates with aging and decline in the replicative potential of the cell: replicative senescence. Telomere DNA of human somatic cells shortens during each cell division thus leading to a finite proliferation. Transfection of the telomerase reverse transcriptase gene results in elongation of telomeres and extension of lifespan. This also applies to humans. Replicative senescence in human cells evolved as a mechanism to protect them from continuous divisions leading to multiple mutations. Longer-lived species such as humans had to develop replicative senescence to ensure that they would have the increased protection that their longevity necessitates.

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Section: Antihypertensive Drugsmentioning

confidence: 99%

Aging Liver

Anantharaju¹,

Feller²,

Chedid³

2002

Gerontology

167

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“…The two enantiomers appear to be equally potent as a,-blockers, but the P-blockade is principally attributable to the S( -)-enantiomer. l5 We have previously found that the nonselective P-blocker propranolol, which is also given as a racemic mixture, is stereoselectively metabolized in humans, [16][17][18] and this stereoselective metabolism is dependent on CYP2D6. l6 If stereoselective metabolism of carvedilol occurs and if that stereoselective metabolism is CYP2D6 dependent, then one would predict that poor metabolizers of debrisoquin (8% of the U.S. population) may respond differently than rapid metabolizers to carvedilol administration.…”

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confidence: 99%

Stereoselective disposition of carvedilol is determined by CYP2D6*

Zhou¹,

Wood²

1995

Clin Pharmacol Ther

123

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Carvedilol is a mixed alpha- and beta-adrenergic receptor antagonist that is administered as a racemic mixture. Although the two isomers are equally potent as alpha 1-blockers the S(-)-isomer is principally responsible for the beta blockade of carvedilol. To determine the role of pharmacogenetics in the metabolism of carvedilol we studied nine extensive metabolizers of both debrisoquin and mephenytoin, seven poor metabolizers of debrisoquin but extensive metabolizers of mephenytoin, and three poor metabolizers of mephenytoin but extensive metabolizers of debrisoquin. The clearance of R-carvedilol was significantly lower than S-carvedilol in both debrisoquin phenotypes. Poor metabolizers of debrisoquin had a significantly lower clearance of R-carvedilol than extensive metabolizers of debrisoquin. The partial metabolic clearance of carvedilol to the two ring-hydroxylated metabolites 4- and 5-hydroxyphenyl carvedilol were significantly reduced in poor metabolizers of debrisoquin. No effect of mephenytoin phenotype on carvedilol kinetics was observed. Thus carvedilol is stereoselectively metabolized in humans, and the clearance of S-carvedilol is higher than that of R-carvedilol. In poor metabolizers of debrisoquin the clearance of R-carvedilol is further reduced, resulting in higher plasma concentrations and perhaps greater alpha-blockade.

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“…Examples include the effects of aging on the metabolism of drugs that are conjugated in the liver prior to excretion and the metabolism of drugs prescribed as racemic mixtures. In contrast, Zhou et al (1992) failed to find any age-related differences in the disposition of propranolol enantiomers. Similarly, a differential response in terms of S-(+) and R- (-) hexobarbital clearance following concurrent administration of rifampicin (rifampin) to young and elderly volunteers has been reported (Smith et al 1991).…”

Section: Future Needsmentioning

confidence: 68%