Clinical Pharmacology Department, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Sanitaria La Princesa (IP), Madrid, Spain.
Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children's Mercy Research Institute (CMRI), Kansas City, Missouri, USA.
Clin Pharmacol Ther. 2023 Nov;114(5):1033-1042. doi: 10.1002/cpt.3012. Epub 2023 Aug 11.
A novel haplotype composed of two non-coding variants, CYP2C18 NM_000772.3:c.31T (rs2860840) and NM_000772.2:c.819+2182G (rs11188059), referred to as "CYP2C:TG," was recently associated with ultrarapid metabolism of various CYP2C19 substrates. As the underlying mechanism and clinical relevance of this effect remain uncertain, we analyzed existing in vivo and in vitro data to determine the magnitude of the CYP2C:TG haplotype effect. We assessed variability in pharmacokinetics of CYP2C19 substrates, including citalopram, sertraline, voriconazole, omeprazole, pantoprazole, and rabeprazole in 222 healthy volunteers receiving one of these six drugs. We also determined its impact on CYP2C8, CYP2C9, CYP2C18, and CYP2C19 protein abundance in 135 human liver tissue samples, and on CYP2C18/CYP2C19 activity in vitro using N-desmethyl atomoxetine formation. No effects were observed according to CYP2C:TG haplotype or to CYP2C191+TG alleles (i.e., CYP2C19 alleles containing the CYP2C:TG haplotype). In contrast, CYP2C19 intermediate (e.g., CYP2C19*1/2) and poor metabolizers (e.g., CYP2C192/2) showed significantly higher exposure in vivo, lower CYP2C19 protein abundance in human liver microsomes, and lower activity in vitro compared with normal, rapid (i.e., CYP2C191/17), and ultrarapid metabolizers (i.e., CYP2C1917/17). Moreover, a tendency toward lower exposure was observed in ultrarapid metabolizers compared with rapid metabolizers and normal metabolizers. Furthermore, when the CYP2C1917 allele was present, CYP2C18 protein abundance was increased suggesting that genetic variation in CYP2C19 may be relevant to the overall metabolism of certain drugs by regulating not only its expression levels, but also those of CYP2C18. Considering all available data, we conclude that there is insufficient evidence supporting clinical CYP2C:TG testing to inform drug therapy.
一种由两个非编码变异组成的新型单倍型，CYP2C18 NM_000772.3：c.31T（rs2860840）和 NM_000772.2：c.819+2182G（rs11188059），被称为“CYP2C：TG”，最近与各种 CYP2C19 底物的超快代谢有关。由于这种影响的潜在机制和临床相关性仍不确定，我们分析了现有的体内和体外数据，以确定 CYP2C：TG 单倍型效应的幅度。我们评估了 222 名健康志愿者接受六种药物之一时 CYP2C19 底物的药代动力学变异性，包括西酞普兰、舍曲林、伏立康唑、奥美拉唑、泮托拉唑和雷贝拉唑。我们还在 135 个人肝组织样本中确定了它对 CYP2C8、CYP2C9、CYP2C18 和 CYP2C19 蛋白丰度的影响，以及使用 N-去甲基Atomoxetine 形成的体外 CYP2C18/CYP2C19 活性。根据 CYP2C：TG 单倍型或 CYP2C191+TG 等位基因（即包含 CYP2C：TG 单倍型的 CYP2C19 等位基因）未观察到影响。相比之下，CYP2C19 中间代谢物（例如 CYP2C19*1/2）和弱代谢物（例如 CYP2C192/2）在体内表现出显著更高的暴露，人肝微粒体中 CYP2C19 蛋白丰度更低，体外活性更低与正常、快速（即 CYP2C191/17）和超快代谢物（即 CYP2C1917/17）相比。此外，与快速代谢物和正常代谢物相比，超快代谢物中观察到暴露倾向降低。此外，当存在 CYP2C1917 等位基因时，CYP2C18 蛋白丰度增加，这表明 CYP2C19 的遗传变异可能与某些药物的整体代谢有关，不仅调节其表达水平，还调节 CYP2C18 的表达水平。考虑到所有可用数据，我们得出的结论是，没有足够的证据支持临床 CYP2C：TG 测试来指导药物治疗。
