Influence of age, frailty and liver function on the pharmacokinetics of brofaromine

Zeeh, Joachim; Fuchs, Luiz Fernando Portugal; Bergmann, W.; Kh, Antonin; Degel, Fritz; Bieck, P. R.; Platt, D.

doi:10.1007/bf00203783

Cited by 11 publications

(2 citation statements)

References 21 publications

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“…Investigations into the effect of age on in vivo activity of CYP1A2, 3A4, 2C9, 2C19 and 2D6 generally report decreases, 18 although not for all substrates. For example, CYP1A2 activity is reported as both unchanged 19,20 and decreased 21,22 with increasing age.…”

Section: Discussionmentioning

confidence: 99%

Alosetron repeat dose pharmacokinetics, effects on enzyme activities, and influence of demographic factors

Koch¹,

Corrigan²,

Manzo³

et al. 2004

Aliment Pharmacol Ther

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SUMMARYAim: To assess the pharmacokinetics of alosetron, its effect on in vivo enzyme activities, and influence of demographic factors during repeated dosing. Methods: Thirty healthy men and women received 1 mg oral alosetron twice-daily for 29.5 days and a single oral dose of a metabolic probe cocktail before and on the last day of alosetron dosing. Serum alosetron concentrations were measured on days 1, 8, 15, 22 and 29. Probe-substrate and metabolite concentrations were measured after each cocktail dose. Results: Alosetron accumulation in serum was negligible. Exposure to alosetron did not alter probemetabolite/substrate ratios associated with CYP2C19, 2E1, 2C9, or 3A4 activity, but modestly decreased those associated with CYP1A2 and N-acetyltransferase activity. Systemic exposure to alosetron was higher in women, positively correlated with age and body mass index, and negatively correlated with CYP1A2 activity. Incidence of constipation was higher in women, but not associated with alosetron concentration. Conclusions: Single dose data can reliably predict the pharmacokinetics of alosetron after repeated doses. Alosetron exhibits limited potential for inhibition of cytochrome P450-mediated metabolism. Interindividual differences in alosetron pharmacokinetics associated with demographic factors may be related to strong dependence on metabolism by CYP1A2.

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Section: Discussionmentioning

confidence: 99%

Alosetron repeat dose pharmacokinetics, effects on enzyme activities, and influence of demographic factors

Koch¹,

Corrigan²,

Manzo³

et al. 2004

Aliment Pharmacol Ther

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“…We had previously shown that CYP1A1-mediated EROD activity was lower in humans over 13 years of age; CYP1A2-mediated EROD was also shown to decrease with age [11]. A decrease in clearance of CYP1A2 substrate in the elderly was observed in other studies [12].…”

mentioning

confidence: 93%

Multivariate cluster analysis of a human hepatic cytochrome P 450 database

Johnston

Class³

et al. 2002

European Journal of Clinical Pharmacology

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The relationship between various co-variates, microsomal enzymatic activities and pharmacokinetic parameters such as clearance and volume of distribution are traditionally evaluated by correlation. This type of analysis determines the relationship between variables in a qualitative manner. The closeness of a variable in relation to another is determined by the correlation coefficient, which lies between 0 and 1. A major drawback of correlation analysis is that the mathematical distance between the two variables is not available. A multiple-linear regression model is often used to further define the relationship between variables. However, analyses using multiple-linear regression models require a specific response variable. In the case where several metabolic pathways are being evaluated, each of the enzymatic activities should then be defined as a response variable. Building several multiple-linear regression models becomes time consuming and redundant. In contrast to multiple-linear regression, cluster analysis does not require a specific response variable. In this study, we used multivariate statistical cluster analysis to provide a mathematical and visual representation of the relationship between various cytochrome P 450 (CYP) isozyme functions and demography in a CYP database. The demographic factors that were known to influence drug metabolism, such as age and gender, were introduced as co-variates in the model.A total of 38 human livers were collected and microsomes were prepared. Of the donors 18 were male and 20 were female. Of these 38, 16 were less than 13 years of age at the time of liver harvest, 16 belonged to the group 13-40 years of age, and 6 were more than 40 years old. The average ages of the male and female donors were 20±16 years and 19±16 years, respectively.Individual liver microsomes were screened for their CYP1A, CYP2E1 and CYP3A4 activities. Total CYP was measured spectrometrically. Ethoxyresorufin Odeethylation (EROD), caffeine 1-demethylation (37X), caffeine 3-demethylation (17X) and phenacetin O-deethylation (POD) were the probes used to determine CYP1A activity at the ethoxyresorufin, phenacetin and caffeine concentrations of 0.42, 200 and 400 lM, respectively. Chlorzoxazone hydroxylation (CzOH) and testosterone 6b-hydroxylation (T6OH) were used to determine CYP2E1 and CYP3A4 activities at 250 lM and 100 lM substrate concentrations, respectively. The phenotypic trait measured via specific probe activity reflects the metabolic clearance in vivo. These isozymes account for more than 70% of human drug metabolism.

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Genomic Variation and Pharmacokinetics in Old Age: A Quantitative Review of Age‐ vs. Genotype‐Related Differences

Dücker

Brockmöller

2018

Clin Pharma and Therapeutics

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Older persons may particularly benefit from pharmacogenetic diagnostics, but there is little clinical evidence on that question. We quantitatively analyzed the effects of age and genotype in drugs with consensus on a therapeutically relevant impact of a genotype. Assuming additive effects of age and genotype, drugs may be classified in groups with different priorities to consider either age, or genotype, or both, in therapy. Particularly interesting were those studies specifically analyzing the age-by-genotype interaction.

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Influence of age, frailty and liver function on the pharmacokinetics of brofaromine

Abstract: Caffeine clearance, a simple, noninvasive test of CYP1A2 activity, is predictive of brofaromine clearance.

Cited by 11 publications

References 21 publications

Alosetron repeat dose pharmacokinetics, effects on enzyme activities, and influence of demographic factors

Alosetron repeat dose pharmacokinetics, effects on enzyme activities, and influence of demographic factors

Multivariate cluster analysis of a human hepatic cytochrome P 450 database

Genomic Variation and Pharmacokinetics in Old Age: A Quantitative Review of Age‐ vs. Genotype‐Related Differences

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