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  3. Sex differences in the metabolic activation of and platelet response to vicagrel in mice: Androgen as a key player

Sex differences in the metabolic activation of and platelet response to vicagrel in mice: Androgen as a key player

  • Biochem Pharmacol. 2024 Oct 2;230(Pt 1):116564. doi: 10.1016/j.bcp.2024.116564.
Li-Ping Jiang 1,  Min Fu 1,  Na Yin 1,  Yu-Meng Jia 2,  Fu-Yang Duan 1,  Lei Feng 1,  Li Yang 1,  Hao-Ru Han 1,  Jin Wang 1,  Ting Zhu 1,  Jin-Zi Ji 3,  Ting Tai 4,  Xue-Mei Li 5,  Zhao-Dong Zheng 1,  Pei-Jie Ding 1,  Ya-Lan Sun 1,  Qiong-Yu Mi 6,  Hong-Guang Xie 7
Affiliations

Affiliations

  • 1 Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, China Pharmaceutical University, Nanjing 210006, China; Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 2 Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, China Pharmaceutical University, Nanjing 210006, China.
  • 3 Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, China Pharmaceutical University, Nanjing 210006, China; Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China.
  • 4 Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, China Pharmaceutical University, Nanjing 210006, China; Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China.
  • 5 Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China.
  • 6 Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, China Pharmaceutical University, Nanjing 210006, China; Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China. Electronic address: miqiongyu@njmu.edu.cn.
  • 7 Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, China Pharmaceutical University, Nanjing 210006, China; Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China. Electronic address: hong-guang.xie@njmu.edu.cn.
PMID: 39366431 DOI: 10.1016/j.bcp.2024.116564
Abstract

As a biological variable, sex influences the metabolism of and/or response to certain drugs. Vicagrel is being developed as an investigational new drug in China; however, it is unknown whether sex could affect its metabolic activation and platelet responsiveness. This study aimed to determine whether such differences could exist, and to elucidate the mechanisms involved. Orchiectomized (ORX) or ovariectomized (OVX) mouse models were used to investigate the effects of androgens or estrogens on the metabolic activation of and platelet response to vicagrel. Plasma vicagrel active metabolite H4 concentrations, platelet inhibition of vicagrel, and protein levels of intestinal hydrolases Aadac and Ces2 were measured, respectively. Further, p38-MAPK signaling pathway was enriched, whose role was determined using SB202190. Results showed that female mice exhibited significantly elevated systemic exposure of H4 and enhanced platelet responses to vicagrel than males, and that protein expression levels of Aadac and Ces2 differed by sex. OVX mice exhibited less changes than sham mice. ORX mice exhibited increases in protein levels of intestinal hydrolases, systemic exposure of H4, and platelet inhibition of vicagrel, but dihydrotestosterone (DHT) reversed these changes in ORX mice and suppressed these changes in OVX mice. Phosphorylated p38 levels were reduced in female or ORX mice but increased in ORX mice by DHT. SB202190 reversed DHT-induced changes observed in ORX mice. We concluded that sex differences exist in metabolic activation of and platelet response to vicagrel in mice through elevation of p38 phosphorylation by androgens, suggesting sex-based vicagrel dosage adjustments for patient care.

Keywords

AADAC; Androgen; CES2; Gender; Platelet; Sex; Vicagrel; p38 MAPK.

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