Interleukin-10 does not modulate clopidogrel platelet response in mice
1General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
Unlabelled:
ESSENTIALS: It is unclear whether interleukin-10 (IL-10) could affect clopidogrel metabolism and response. The bioactivation of and response to clopidogrel were determined between mice with or without IL-10. Maximum clopidogrel active metabolite levels were the major driver of platelet response to clopidogrel. IL-10 did not modulate maximum levels of clopidogrel active metabolite and its antiplatelet effects.
Background:
Elevated plasma interleukin-10 (IL-10) levels were observed in patients who responded less to clopidogrel (a prodrug that is required for further metabolic bioactivation in the liver). However, no data are currently available suggesting whether there is such an association.
Objective:
To systematically explore possible differences in the formation of and response to clopidogrel active metabolite (CAM) in mice with or without IL-10 gene expression.
Methods:
A single oral dose of clopidogrel (10 mg kg(-1)) was given to IL-10 knockout (KO) mice and wild-type (WT) control mice, respectively, and pharmacokinetic parameters of clopidogrel and CAM were calculated. Moreover, adenosine diphosphate-induced whole-blood platelet aggregation was measured in mice receiving 0, 5, 10, or 20 mg kg(-1) of clopidogrel, respectively.
Results:
Compared with IL-10 KO mice, WT mice had significantly lower area under the plasma concentration-time curve (AUC) of CAM as a result of a shorter mean elimination half-life but had significantly higher AUC of clopidogrel due to slower systemic clearance and smaller volume of distribution. Although AUC of CAM was significantly lower in WT mice than in KO mice, antiplatelet effects of clopidogrel did not differ significantly between the two mouse groups, as their maximum plasma concentrations (Cmax ) of CAM were not significantly different.
Conclusions:
IL-10 expression level affects AUC rather than Cmax of CAM, but the Cmax of CAM is the major driver of antiplatelet effects of clopidogrel in mice.
Insights
Interleukin-10 (IL-10) does not affect the maximum levels of clopidogrel active metabolite (CAM) or its antiplatelet effects. CAM’s maximum concentration, not its overall exposure, is key to clopidogrel
Area of Science:
- Pharmacology and Toxicology
- Immunology
- Drug Metabolism
Background:
- Elevated interleukin-10 (IL-10) levels correlate with reduced clopidogrel response in patients.
- Clopidogrel requires hepatic bioactivation to exert its antiplatelet effects.
- No prior data existed on the direct association between IL-10 and clopidogrel metabolism or efficacy.
Purpose of the Study:
- To investigate the impact of IL-10 gene expression on clopidogrel active metabolite (CAM) formation.
- To determine if IL-10 influences the antiplatelet response to clopidogrel.
- To compare clopidogrel pharmacokinetics and pharmacodynamics in IL-10 knockout and wild-type mice.
Main Methods:
- Administered a single oral dose of clopidogrel to IL-10 knockout and wild-type mice.
- Quantified clopidogrel and CAM pharmacokinetic parameters, including area under the curve (AUC) and maximum concentration (Cmax).
- Assessed adenosine diphosphate-induced platelet aggregation to measure antiplatelet effects.
Main Results:
- Wild-type mice showed lower CAM AUC and shorter half-life compared to IL-10 knockout mice.
- Clopidogrel AUC was higher in wild-type mice, indicating slower clearance.
- Despite differences in CAM AUC, antiplatelet effects did not significantly differ due to comparable CAM Cmax between groups.
Conclusions:
- IL-10 influences the overall exposure (AUC) of clopidogrel active metabolite (CAM), but not its peak concentration (Cmax).
- The maximum concentration (Cmax) of CAM is the primary determinant of clopidogrel's antiplatelet activity in mice.
- IL-10 status does not significantly alter the therapeutic efficacy of clopidogrel in this mouse model.
