Age and cytochrome P450-linked drug metabolism in humans: an analysis of 226 subjects with equal histopathologic conditions (original) (raw)
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Effects of age increase on hepatic expression and activity of cytochrome P450 in male C57BL/6 mice
Archives of pharmacal research, 2014
Effects of aging on hepatic expression and activity of cytochrome P450 (CYP) isoforms were investigated in male mice aged 2, 6, 18, and 30 months. Microsomal protein, total CYP, cytochrome b5 and NADPH-dependent cytochrome P450 reductase contents in liver were fully expressed in young (2-month-old) mice. Neither Cyp1a1 nor Cyp2c was detected in any aged mice. And Cyp1a2 was maximally expressed at 2 months and decreased with age. Hepatic levels of Cyp2b10 and Cyp3a11 were decreased in 30-month-old mice. Hepatic Cyp2e1 levels were constantly maintained from 2-month to 30-month old mice. Hepatic activities of ethoxyresorufin-O-deethylase and methoxyresorufin-O-demethylase were gradually decreased after 6 months. The 30-month-old mice exhibited the lowest activity of midazolam 1'-hydroxylase. Pentoxyresorufin-O-depenthylase activity was decreased in 30-month-old mice, but not statistically significant. There were no significant differences in hepatic activities of chlorzoxazone 6-hy...
The Effect of Age and Sex on Metabolism and Urinary Excretion of Antipyrine
The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 1998
Background. Drug-metabolizing capacity is generally reduced in the elderly. The purpose of this investigation was to study antipyrine clearance and metabolite excretion in old subjects of both sexes. Methods. Saliva clearance of antipyrine and the production clearances of antipyrine metabolites were studied in young and elderly volunteers of both sexes. Seventy-six elderly subjects (mean age 81 years) were compared with a group of 24 young subjects (mean age 29 years). Results. After oral administration, salivary antipyrine clearance declined with age in both males and females, whether or not this variable was corrected for weight, and antipyrine half-life was significantly prolonged in elderly groups of either sex. The percentage urinary excretion of the antipyrine metabolites (hydroxymethylantipyrine, HMA; norantipyrine, NORA; and 4-hydroxyantipyrine, OHA) was reduced at 48 h in the elderly compared to young subjects by 23%, 31%, and 10%, respectively, in males, and by 41%, 41%, and 24%, respectively, in females. The formation clearance of HMA was reduced by 47% in males and by 52% in females. NORA clearance declined by 42 and 56%, respectively, in males and females. A decrease of 30% in males and 44% in females was observed in OHA clearance. Conclusions. The findings suggest that aging leads to altered disposition of antipyrine in both males and females and that the main metabolic pathways of the compound are not different in the elderly.
Pharmacogenetics of cytochrome P450 (CYP) in the elderly
Ageing Research Reviews, 2010
The genetics of cytochrome P450 (CYP) is a very active area of multidisciplinary research, overlapping the interest of medicine, biology and pharmacology, being the CYP enzyme system responsible for the metabolism of more than 80% of the commercially available drugs. Variations in CYP encoding genes are responsible for inter-individual differences in CYP production or function, with severe clinical consequences as therapeutic failures (TFs) and adverse drug reactions (ADRs), being ADRs worldwide primary causes of morbidity and mortality in elderly people. In fact, the prevalence of both TFs and ADRs strongly increased in the presence of multiple pharmacological treatments, a common status in subjects aging 65 years and over. The present article explored some basic concepts of human genetics that have important implications in the genetics of CYP. An attempted to transfer these basic concepts to the genetic data reported by the Home Page of The Human Cytochrome P450 (CYP) Allele Nomenclature Committee was also made, focusing on the current knowledge of CYP genetics. The status of what we know and what we need to know is the base for the clinical applications of pharmacogenetics, in which personalized drug treatments constituted the main aim, in particular in patients attending a geriatric ward.
Effects of Aging on Antipyrine Clearance: Predictive Factors of Metabolizing Capacity
The Journal of Clinical Pharmacology, 1995
and that may help predict a reduction in metabolizing capacity. For comparison, ClAp was determined in 177 elderly (mean age 82 years) and 25 young (mean age 29 years) volunteers. Antipyrine (1 g) was administered orally and ClAP was determined by the one-sample saliva method. Mean ClAp was reduced by 38% and antipyrine half-lifeincreased by 64% in old subjects. Multiple regression analysis of ClAP revealed an independent value for age, serum aspartate transaminase (AST), and height in the elderly. The independent variables collectively accounted for 27% of the variance explained. Age, high serum AST, half-lives of antipyrine have been reported in subjects older than 65 years of age than in those younger than 40 years of age.2-9 Even when age effects are demonstrated, the possibility remains that differ-From
Drug metabolism in older peoplea key consideration in achieving optimal outcomes with medicines
The Journals …, 2011
Hepatic clearance plays a key role in determining the systemic exposure of drugs and metabolites, which in turn has a major effect on variability in the beneficial and adverse effects of medicines. Aging results in a number of significant changes in the human liver including reductions in liver blood flow, size, drug-metabolizing enzyme content, and pseudocapillarization. Drug metabolism is also influenced by comorbid disease, frailty, concomitant medicines, and (epi) genetics. These changes have the potential to alter the hepatic clearance of drugs but need to be interpreted in the context of the pharmacokinetic (and pharmacodynamic) characteristics of the drug of interest. There is growing evidence that the age-related changes in the liver not only result in a decrease in the hepatic clearance of unbound drug but also influence variability in response to medicines in older people.
Relationship between in vivo and in vitro drug metabolism in man
European Journal of Drug Metabolism and Pharmacokinetics, 1978
Relationship between in vivo and in vitro drug metabolism was investigated in 200 consecutive patients with diagnostic liver needle biopsy by comparing the cytochrome P-450 (P-450) content in biopsies with the elimination kinetics of antipyrine. P-450 level in livers varied from 0.5 to 32.5 nmole/g, it was increased in subjects treated with enzyme inducing drugs and reduced in patients with degenerative parenchymal changes in the liver. Antipyrine metabolism also varied markledy, the half-life ranged from 2.2 to 54.4 hrs and the clearance from 3.5 to 142.4 ml/min. Rapid drug metabolism was associated with subjects with normal liver or with slight liver changes in case they were also treated with known inducers whereas reduced antipyrine metabolism was seen in subjects with degenerative liver changes. P-450 content in biopsies was related to the kinetic parameters of antipyrine: correlation between P-450 in livers and the drug clearance was linear whereas a non-linear relationship between P-450 and plasma half-life was obtained. The results demonstrate a relationship between in vivo and in vitro parameters of drug metabolism in man and show the importance of liver parenchymal changes and drug therapy as factors influencing hepatic drug metabolism.
Altered drug metabolism in hepatic and extrahepatic tissues in mice as a function of age
AGE, 1980
An increase in the susceptibility to drugs is known to occur with advanced age. Several possible explanations for this phenomenon exist, but the exact cause has not been determined. Aryl hydro. carbon hydroxylase (AHH), 7.ethoxycoumarin O.deethylase (ECD) and aniline hydroxylase ac. tivities of hepatic and extrahepatic tissues as well as hepatic cytochrome P.450 content of female Swiss Webster mice at 1, 3, 6, 9, 12, 15 and 18 months of age were examined. AHH activity in liver and intestine reached a maximum at 6 mo. of age and began to decline thereafter. No change in pulmonary AHH activity was observed with age. ECD activity in liver as well as lungs was maximal at 6 mo. of age and decreased thereafter. Hepatic aniline hydroxylase activity exhibited over a 700% increase between one to six mo. of age, and declined by approximately 52% by 15 mo. of age as compared to peak activity. Hepatic cytochrome P-450 content was highest at 3 mo. of age and significantly decreased by 12 mo. The results demonstrate that decreases in microsomal mixed function monooxygenase activities do occur with advanced age and may contribute to a decreased rate of metabolism and increased susceptibility to drugs and other foreign chemicals with age.
Drug Metabolism and Disposition, 2003
Numerous studies, usually limited to male rodents, have reported an inverse relationship between the age of the animal and the activities of various multi-cytochrome P450-dependent drug-metabolizing enzymes. It has been suggested that the aging-induced decline in hepatic drug-metabolizing capacity is solely a male phenomenon. That is, whereas the levels of male-specific isoforms of P450 decline with senescence, the female-dependent isoforms remain unchanged in females and even increase in male liver. In addition to their baseline activities, induction levels of hepatic monooxygenases have also been reported to decrease with aging. To examine aging-and sex-dependent effects on drug metabolism at a more molecular level, we measured the expression (mRNA, protein, and/or catalytic activity) of a near dozen constitutive and inducible isoforms of P450 in 5-and 23-month-old male and female Sprague-Dawley rats. Moreover, we investigated the induction effects of low concentrations of phenobarbital known to reveal gender differences and the threshold sensitivities of both constitutive and inducible isoforms. With the exception of male-specific CYP2C11 (whose expression declined ϳ70% in aged male rats), we observed little senescence-associated reduction in either preinduction or induction levels of CYP2B1, CYP2B2, CYP3A1, CYP3A2, CYP2C6, CYP2C7, CYP2C12, and CYP2C13 in either male or female rats. Moreover, the sexually dimorphic expression levels apparent at 5 months of age persisted in the old rats.