Key result
Older human liver microsomes generate ~11% less clopidogrel active metabolite than younger tissue.
Why the study?
High on-treatment platelet reactivity on clopidogrel occurs frequently in elderly patients, but mechanisms behind potential age-related impaired hepatic metabolism to its active metabolite remain unclear.
Does in vitro clopidogrel metabolism by older human liver microsomes reduce the formation of active metabolite compared to younger microsomes?
Does in vitro clopidogrel metabolism by older human liver microsomes reduce the formation of active metabolite compared to younger microsomes?
Standardized Mean Difference: 0.35
Absolute Event Rate: 7.64% vs 8.56%
p-value: p=0.002
Age-related decline in hepatic CYP450 metabolism significantly reduces the in vitro generation of clopidogrel's active metabolite, offering a mechanistic explanation for high on-treatment platelet reactivity in the elderly.
May explain higher on-treatment platelet reactivity in elderly; hypothesis-generating for age-specific antiplatelet regimens.
Background: High on-treatment platelet reactivity has been reported in 30% of patients on clopidogrel and 50% in elderly patients; however, little is known about the mechanisms of this biological resistance. One hypothesis is an age-related impaired hepatic metabolism of the prodrug clopidogrel, leading to a lower formation of its active metabolite (clopidogrel-AM). Objectives: using "old" and "young" human liver microsomes (HLMs) and their consequences on platelet functions. Methods: model using "old" (73.6 ± 2.3 years) and "young" (51.2 ± 8.5 years) HLMs, added to platelet-rich plasma from 21 healthy donors with or without clopidogrel (50 μM) and incubated at 37 °C for 30 (T30) and 45 minutes (T45). Clopidogrel-AM was quantified by liquid chromatography-mass spectrometry/mass spectrometry method. Platelet aggregation was performed by light transmission aggregometry. Despite a significant inhibition of platelet aggregation, no significant difference was found in light transmission aggregometry (adenosine diphosphate, 10 μM) after clopidogrel metabolism by "old" or "young" HLMs, probably because of low sensitivity of the method to small variations of clopidogrel-AM. Conclusion: In this original model combining metabolic and functional approaches, less clopidogrel-AM was produced with HLMs from older patients. This provides support for a decreased CYP450 activity that may contribute to high on-treatment platelet reactivity in elderly patients.
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Pontis et al. (2023) studied Healthy volunteers (blood donors for in vitro assay) (n=21). Old human liver microsomes (age ≥70) vs. Young human liver microsomes (age <70) was evaluated on Levels of clopidogrel active metabolite (clopidogrel-AM) formed at 30 minutes (Cohen's d 0.35, p=0.002). Incubation of clopidogrel with old human liver microsomes produced significantly less active metabolite at 30 minutes compared to young microsomes (7.64 vs 8.56 μg/L, p=0.002).
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