Aging-Related CYP3A Functional Changes in Chinese Older Patients: New Findings from Model-Based Assessment of Amlodipine.
Humans
Amlodipine
/ pharmacokinetics
Aged
Cytochrome P-450 CYP3A
/ metabolism
Male
Female
Aging
/ metabolism
Aged, 80 and over
Asian People
Models, Biological
Antihypertensive Agents
/ pharmacokinetics
China
Middle Aged
Age Factors
Liver
/ metabolism
Frail Elderly
Calcium Channel Blockers
/ pharmacokinetics
East Asian People
Journal
Clinical pharmacology and therapeutics
ISSN: 1532-6535
Titre abrégé: Clin Pharmacol Ther
Pays: United States
ID NLM: 0372741
Informations de publication
Date de publication:
Sep 2024
Sep 2024
Historique:
received:
31
01
2024
accepted:
04
06
2024
medline:
21
8
2024
pubmed:
21
8
2024
entrez:
21
8
2024
Statut:
ppublish
Résumé
Aging-related alterations in hepatic enzyme activity, particularly of the CYP3A, significantly impact drug efficacy and safety in older adults, making it essential to understand how aging affects CYP function for optimal drug therapy. The exogenous probe substrate method, a minimally invasive approach to assess liver metabolic enzyme activity in vivo, is effective in studying these changes. Amlodipine being extensively metabolized (> 90%) in the liver, primarily via cytochrome P450 enzyme CYP3A was selected as a probe to investigate and quantify the factors affecting the aging-related changes of CYP3A in the Chinese older population. Amlodipine concentration data were collected from an ongoing noninterventional clinical study conducted at Peking University Third Hospital. A physiologically-based pharmacokinetic modeling approach, grounded in population pharmacokinetic (PPK) analysis, was employed to physiologically quantify the aging-related changes in CYP3A function. A total of 132 amlodipine concentrations from 69 patients were obtained from the clinical study. PPK analysis shows that frailty phenotype but not age is a significant influence and frail patients have 37% greater plasma amlodipine exposure than nonfrail patients. This difference in CYP3A function may be attributed to a 63.2% lower CYP3A relative abundance in the frail patients, compared with that in the nonfrail patients. In the context of dose selection for older adults, focusing on frailty rather than chronological age should be recognized as a more relevant approach, because frailty might more accurately reflect the individual's biological age. Our study suggested a need to shift the research focus from chronological age to biological age.
Substances chimiques
Amlodipine
1J444QC288
Cytochrome P-450 CYP3A
EC 1.14.14.1
Antihypertensive Agents
0
CYP3A protein, human
EC 1.14.14.1
Calcium Channel Blockers
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
858-865Subventions
Organisme : National Natural Science Foundation of China
ID : 82104293
Organisme : Bill & Melinda Gates Foundation
ID : INV-007625
Pays : United States
Informations de copyright
© 2024 The Author(s). Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.
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