Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, China Pharmaceutical University, Nanjing, China; Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
J Thromb Haemost. 2023 May;21(5):1322-1335. doi: 10.1016/j.jtha.2023.01.028. Epub 2023 Feb 2.
T cells and platelets reciprocally coordinate mutual functions through crosstalk or interaction. However, it is not known whether metabolic activation of and platelet response to clopidogrel could be changed if T cells were deficient or impaired in some cases and, if any, how it would work.
The objective of this study was to dissect the potential changes in platelet responses to and metabolic activation of clopidogrel in the case of T cell deficiency and to elucidate their mechanisms involved.
BALB/c athymic nude mice or euthymic mice (controls) pretreated with cyclosporine A (CsA), thymosin α1 (Tα1), or their combination were used to investigate the changes in ADP-induced platelet activation and aggregation, systemic exposure of clopidogrel and its metabolites, and mRNA/protein expression and activity levels of clopidogrel-metabolizing enzymes in the liver, respectively.
Nude mice exhibited significantly enhanced antiplatelet effects of clopidogrel due to increased formation of clopidogrel active metabolite in the liver, where the enzyme activity levels of Cyp2c and Cyp3a were significantly elevated compared with control mice. Furthermore, the effects of CsA pretreatment on the metabolism of clopidogrel in euthymic mice were identical to those seen in athymic mice. As expected, concomitant use of Tα1 reversed all the observed effects of CsA on clopidogrel metabolism and relevant metabolic enzymes.
T cell deficiency or suppression enhances the antiplatelet effects of clopidogrel due to the boosted metabolic activation of clopidogrel in the liver through a dramatic induction of Cyp2c and Cyp3a in mice, suggesting that the metabolism of substrate drugs of Cyp2c and Cyp3a may be enhanced by T cell impairment.
T 细胞和血小板通过串扰或相互作用相互协调彼此的功能。然而，目前尚不清楚在 T 细胞缺乏或受损的情况下，血小板对氯吡格雷的反应和代谢激活是否会发生变化，如果会，其作用机制如何。
本研究旨在剖析 T 细胞缺乏时血小板对氯吡格雷反应和代谢激活的潜在变化，并阐明其涉及的机制。
使用 BALB/c 无胸腺裸鼠或同型正常鼠（对照组），分别用环孢素 A（CsA）、胸腺肽 α1（Tα1）或两者联合预处理，以研究 ADP 诱导的血小板激活和聚集、氯吡格雷及其代谢物的全身暴露以及肝脏中氯吡格雷代谢酶的 mRNA/蛋白表达和活性水平的变化。
裸鼠由于肝脏中氯吡格雷活性代谢物形成增加，表现出明显增强的氯吡格雷抗血小板作用，其中 Cyp2c 和 Cyp3a 的酶活性水平明显高于对照组小鼠。此外，CsA 预处理对同型正常鼠氯吡格雷代谢的影响与裸鼠相同。不出所料，同时使用 Tα1 逆转了 CsA 对氯吡格雷代谢及相关代谢酶的所有观察到的作用。
T 细胞缺乏或抑制通过在小鼠肝脏中显著诱导 Cyp2c 和 Cyp3a，增强氯吡格雷的代谢激活，增强了氯吡格雷的抗血小板作用，提示 Cyp2c 和 Cyp3a 底物药物的代谢可能因 T 细胞损伤而增强。
